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Elkotamy MS, Elgohary MK, Maher A, Alkabbani MA, Almehizia AA, Naglah AM, Ghabbour HA, Eldehna WM, Abdel-Aziz HA. Development of Benzothiazole-grafted Pyrazolo[1,5-a]pyrimidines as new CDK2 inhibitors and anti-prostate cancer agents. Bioorg Chem 2025; 161:108565. [PMID: 40359842 DOI: 10.1016/j.bioorg.2025.108565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/19/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025]
Abstract
In the current medical era, CDK2 kinase has emerged as a promising target in the global fight against cancer. Recent research reported the overexpression of CDK2 in prostate cancer cells, which highlighted the potential of CDK2 inhibition as a practical therapeutic approach for this disease that stands out as a challenging global health issue. On account of their interesting biological activities, especially anti-cancer properties, the two privileged scaffolds benzothiazole and pyrazolo[1,5-a]pyrimidine were utilized in this study to develop three series of 16 novel small molecules (8a-k, 12a-c, and 14a-b) as potential anti-prostate cancer agents targeting CDK2. The synthesized derivatives were assessed for cytotoxic effects against two prostate cancer cell lines, DU-145 and PC-3. Compounds 8f, 12c, and 14b exhibited the highest anti-cancer activity. Further investigation showed that these molecules inhibit critical cell cycle regulators by arresting DU-145 cells at the G0/G1 phase. Apoptosis induction was verified using Annexin V-FITC/Propidium iodide (PI) assays, which indicated a noteworthy apoptosis level in DU-145 cells. The compounds were validated as CDK2 inhibitors via in-vitro assays, with 8f demonstrating the highest potency, exceeding that of the reference drug Roscovitine. Molecular docking studies revealed substantial binding affinities of compounds 8f, 12c, and 14b to the ATP-binding site of CDK2, supported by essential hydrogen bonding and hydrophobic interactions. Overall, these study's findings indicate the potential of these benzothiazole-grafted pyrazolo[1,5-a]pyrimidines as effective therapeutic agents for prostate cancer.
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Affiliation(s)
- Mahmoud S Elkotamy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt.
| | - Mohamed K Elgohary
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Arwa Maher
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Mahmoud Abdelrahman Alkabbani
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt
| | - Abdulrahman A Almehizia
- Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Ahmed M Naglah
- Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
| | - Hazem A Ghabbour
- School of Health and Biomedical Sciences, RMIT University, Melbourne 3083, Australia.
| | - Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt
| | - Hatem A Abdel-Aziz
- Applied Organic Chemistry Department, National Research Center, Dokki 12622, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St, Alexandria 21648, Egypt
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Chaudhary B, Arya P, Sharma V, Kumar P, Singla D, Grewal AS. Targeting anti-apoptotic mechanisms in tumour cells: Strategies for enhancing Cancer therapy. Bioorg Chem 2025; 159:108388. [PMID: 40107036 DOI: 10.1016/j.bioorg.2025.108388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.
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Affiliation(s)
- Benu Chaudhary
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Preeti Arya
- Shri Ram College of Pharmacy, Ramba, Karnal, Haryana, India
| | - Vikas Sharma
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
| | - Parveen Kumar
- NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan, India
| | - Deepak Singla
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India
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Subbiahanadar Chelladurai K, Selvan Christyraj JD, Rajagopalan K, Vadivelu K, Chandrasekar M, Das P, Kalimuthu K, Balamurugan N, Subramanian V, Selvan Christyraj JRS. Ex vivo functional whole organ in biomedical research: a review. J Artif Organs 2025; 28:131-145. [PMID: 39592544 DOI: 10.1007/s10047-024-01478-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/29/2024] [Indexed: 11/28/2024]
Abstract
Model systems are critical in biomedical and preclinical research. Animal and in vitro models serve an important role in our current understanding of human physiology, disease pathophysiology, and therapy development. However, if the system is between cell culture and animal models, it may be able to overcome the knowledge gap that exists in the current system. Studies employing ex vivo organs as models have not been thoroughly investigated. Though the integration of other organs and systems has an impact on many biological mechanisms and disorders, it can add a new dimension to modeling and aid in the identification of new possible therapeutic targets. Here, we have discussed why the ex vivo organ model is desirable and the importance of the inclusion of organs from diverse species, described its historical aspects, studied organs as models in scientific research, and its ex vivo stability. We also discussed, how an ex vivo organ model might help researchers better understand organ physiology, as well as organ-specific diseases and therapeutic targets. We emphasized how this ex vivo organ dynamics will be more competent than existing models, as well as what tissues or organs would have potentially viable longevity for ex vivo modeling including human tissues, organs, and/or at least biopsies and its possible advantage in clinical medicine including organ transplantation procedure and precision medicine.
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Affiliation(s)
- Karthikeyan Subbiahanadar Chelladurai
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
- School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN, 47907, USA
| | - Jackson Durairaj Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
| | - Kamarajan Rajagopalan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kayalvizhi Vadivelu
- Department of Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Meikandan Chandrasekar
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Puja Das
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kalishwaralal Kalimuthu
- Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Thiruvananthapuram, Kerala, India
| | - Nivedha Balamurugan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Vijayalakshmi Subramanian
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Johnson Retnaraj Samuel Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
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Wang J, Liu ZX, Huang ZH, Wen J, Rao ZZ. Long non-coding RNA in the regulation of cell death in hepatocellular carcinoma. World J Clin Oncol 2025; 16:104061. [PMID: 40290684 PMCID: PMC12019274 DOI: 10.5306/wjco.v16.i4.104061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/02/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for 90% of all cases. Currently, early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection, B-ultrasound, and computed tomography scanning; however, their specificity and sensitivity are suboptimal. Despite significant advancements in HCC biomarker detection, the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis. Therefore, it is crucial to explore more sensitive HCC biomarkers for improved diagnosis, monitoring, and management of the disease. Long non-coding RNA (lncRNA) serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity. Moreover, investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC. We searched the PubMed database for literature, comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells. Furthermore, we prospectively summarize its potential implications in diagnosing and treating HCC.
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Affiliation(s)
- Jiang Wang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zi-Xuan Liu
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhi-Hong Huang
- Children Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Jie Wen
- Department of Pediatric Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhou-Zhou Rao
- Department of Physiology, Hunan Normal University School of Medicine, Changsha 410003, Hunan Province, China
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Bidgoli AD, Farmany A, Taheri M, Soleimani M, Nouri F. Preparation and characterization of calcium-doped graphene oxide-chitosan Nanocarrier to enhance the gene delivery in MCF-7 cell line. Sci Rep 2024; 14:27434. [PMID: 39521829 PMCID: PMC11550409 DOI: 10.1038/s41598-024-78958-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
Gene delivery has emerged as a novel and effective method in the treatment of malignancies within medical interventions by applying nanotechnology. Consequently, the development of appropriate nanocarriers is a key focus of this research. Dynamic light scattering (DLS), fourier transform infrared (FT-IR) spectroscopy, x-ray diffraction (XRD), and thermal gravimetric analysis (TGA) were employed for the characterization of the synthesized nanocarrier. Furthermore, to assess the gene transfer capability of the nanocarrier, various techniques such as gel retardation assay, nuclease resistance assay, cytotoxicity assay, flow cytometry, and transfection were employed. The average particle size and zeta potential of the GO-CS@Ca nanocarrier were obtained as 319.8 nm and + 92.8 mv, respectively. In the gel retardation test, it was observed that pDNA was effectively condensed by the GO-CS@Ca nanocarrier. The results of the MTT assay indicated that both GO-CS@Ca nanocarrier and the GO-CS@Ca/pDNA nanoplex with low toxicity. In flow cytometry analysis, it was observed that the complexation of pDNA with the GO-CS@Ca nanocarrier resulted in effective gene delivery to the MCF-7 cell line and consequently increased apoptosis induction.
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Affiliation(s)
- Amirreza Diari Bidgoli
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Abbas Farmany
- Dental Implant Research Center, Dental School, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Taheri
- Department of Medical Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Nouri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
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Yin T, Zhang X, Xiong Y, Li B, Guo D, Sha Z, Lin X, Wu H. Exploring gut microbial metabolites as key players in inhibition of cancer progression: Mechanisms and therapeutic implications. Microbiol Res 2024; 288:127871. [PMID: 39137590 DOI: 10.1016/j.micres.2024.127871] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/19/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024]
Abstract
The gut microbiota plays a critical role in numerous biochemical processes essential for human health, such as metabolic regulation and immune system modulation. An increasing number of research suggests a strong association between the gut microbiota and carcinogenesis. The diverse metabolites produced by gut microbiota can modulate cellular gene expression, cell cycle dynamics, apoptosis, and immune system functions, thereby exerting a profound influence on cancer development and progression. A healthy gut microbiota promotes substance metabolism, stimulates immune responses, and thereby maintains the long-term homeostasis of the intestinal microenvironment. When the gut microbiota becomes imbalanced and disrupts the homeostasis of the intestinal microenvironment, the risk of various diseases increases. This review aims to elucidate the impact of gut microbial metabolites on cancer initiation and progression, focusing on short-chain fatty acids (SCFAs), polyamines (PAs), hydrogen sulfide (H2S), secondary bile acids (SBAs), and microbial tryptophan catabolites (MTCs). By detailing the roles and molecular mechanisms of these metabolites in cancer pathogenesis and therapy, this article sheds light on dual effects on the host at different concentrations of metabolites and offers new insights into cancer research.
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Affiliation(s)
- Tianxiang Yin
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Xiang Zhang
- Medical School, Yan'an University, Yan'an 716000, China
| | - Yan Xiong
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Bohao Li
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Dong Guo
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Zhou Sha
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Xiaoyuan Lin
- Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing 400038, China.
| | - Haibo Wu
- School of Life Sciences, Chongqing University, Chongqing 401331, China.
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Hamaguchi R, Isowa M, Narui R, Morikawa H, Okamoto T, Wada H. How Does Cancer Occur? How Should It Be Treated? Treatment from the Perspective of Alkalization Therapy Based on Science-Based Medicine. Biomedicines 2024; 12:2197. [PMID: 39457509 PMCID: PMC11504456 DOI: 10.3390/biomedicines12102197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024] Open
Abstract
This review article investigates the relationship between mitochondrial dysfunction and cancer progression, emphasizing the metabolic shifts that promote tumor growth. Mitochondria are crucial for cellular energy production, but they also play a significant role in cancer progression by promoting glycolysis even under oxygen-rich conditions, a phenomenon known as the Warburg effect. This metabolic reprogramming enables cancer cells to maintain an alkaline internal pH and an acidic external environment, which are critical for their proliferation and survival in hypoxic conditions. The article also explores the acidic tumor microenvironment (TME), a consequence of intensive glycolytic activity and proton production by cancer cells. This acidic milieu enhances the invasiveness and metastatic potential of cancer cells and contributes to increased resistance to chemotherapy. Alkalization therapy, which involves neutralizing this acidity through dietary modifications and the administration of alkalizing agents such as sodium bicarbonate, is highlighted as an effective strategy to counteract these adverse conditions and impede cancer progression. Integrating insights from science-based medicine, the review evaluates the effectiveness of alkalization therapy across various cancer types through clinical assessments. Science-based medicine, which utilizes inductive reasoning from observed clinical outcomes, lends support to the hypothesis of metabolic reprogramming in cancer treatment. By addressing both metabolic and environmental disruptions, this review suggests that considering cancer as primarily a metabolic disorder could lead to more targeted and effective treatment strategies, potentially improving outcomes for patients with advanced-stage cancers.
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Affiliation(s)
- Reo Hamaguchi
- Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan; (R.H.); (M.I.); (R.N.); (H.M.)
| | - Masahide Isowa
- Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan; (R.H.); (M.I.); (R.N.); (H.M.)
| | - Ryoko Narui
- Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan; (R.H.); (M.I.); (R.N.); (H.M.)
| | - Hiromasa Morikawa
- Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan; (R.H.); (M.I.); (R.N.); (H.M.)
| | - Toshihiro Okamoto
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Hiromi Wada
- Japanese Society on Inflammation and Metabolism in Cancer, 119 Nishioshikouji-cho, Nakagyo-ku, Kyoto 604-0842, Japan; (R.H.); (M.I.); (R.N.); (H.M.)
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Mangrum DS, Finley SD. Modeling the heterogeneous apoptotic response of caspase-mediated signaling in tumor cells. J Theor Biol 2024; 590:111857. [PMID: 38797470 DOI: 10.1016/j.jtbi.2024.111857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/01/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Resisting apoptosis is a hallmark of cancer. For this reason, it may be possible to force cancer cells to die by targeting components along the apoptotic signaling pathway. However, apoptosis signaling is challenging to understand due to dynamic and complex behaviors of ligands, receptors, and intracellular signaling components in response to cancer therapy. In this work, we forecast the apoptotic response based on the combined impact of these features. We expanded a previously established mathematical model of caspase-mediated apoptosis to include extracellular activation and receptor dynamics. In addition, three potential threshold values of caspase-3 necessary for the activation of apoptosis were selected to forecast which cells become apoptotic over time. We first vary ligand and receptor levels with the number of intracellular signaling proteins remaining consistent. Then, we vary the intracellular protein molecules in each simulated tumor cell to forecast the response of a heterogeneous population. By leveraging the benefits of computational modeling, we investigate the combined effect of several factors on the onset of apoptosis. This work provides quantitative insights for how the apoptotic signaling response can be forecasted, and precisely triggered, amongst heterogeneous cells via extracellular activation.
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Affiliation(s)
- Diamond S Mangrum
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
| | - Stacey D Finley
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
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Elzanaty KA, Omran GA, Elmahallawy EK, Albrakati A, Saleh AA, Dahran N, Alhegaili AS, Salahuddin A, Abd-El-Azim H, Noreldin A, Okda TM. Design and Optimization of Sesamol Nanosuspensions to Potentiate the Anti-Tumor Activity of Epirubicin against Ehrlich Solid Carcinoma-Bearing Mice. Pharmaceutics 2024; 16:937. [PMID: 39065634 PMCID: PMC11279961 DOI: 10.3390/pharmaceutics16070937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/28/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
There is a growing interest in discovering natural sources of anti-cancer drugs. Sesamol (SES) is a phenolic compound with antitumor effects. The present study aimed to investigate the anticancer properties of SES and its nano-suspensions (SES-NS) combined with Epirubicin (EPI) in breast cancer (BC) using mice bearing a solid Ehrlich tumor. The study involved 35 female albino mice and investigated the effects of SES and EPI on tumor growth, proliferation, apoptosis, autophagy, angiogenesis, and oxidative stress. Methods including ELISA, qRT-PCR, and immunohistochemistry were utilized. The findings revealed reductions in tumor growth and proliferation using SES either alone or combined and evidenced by decreased AKT (AKT Serine/Threonine kinase1) levels, angiogenesis indicated by lower levels of VEGFR (vascular endothelial growth factor), and apoptosis demonstrated by elevated caspase3 and BAX levels. Furthermore, autophagy increased and was indicated by increased levels of beclin1 and lc3, along with decreased oxidative stress as evidenced by elevated TAC (total antioxidant capacity) and reduced MDA (malondialdehyde) levels. Interestingly, SES-NS demonstrated more significant effects at lower doses. In summary, this study underscores the potential of SES as a promising agent for BC treatment. Moreover, SES-NS potentiated the beneficial effects of EPI while mitigating its adverse effects.
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Affiliation(s)
- Kholoud A. Elzanaty
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt (T.M.O.)
| | - Gamal A. Omran
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt (T.M.O.)
| | - Ehab Kotb Elmahallawy
- Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), Departamento de Sanidad Animal, Universidad de Córdoba, 14071 Córdoba, Spain
- Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt
| | - Ashraf Albrakati
- Department of Human Anatomy, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Ayman A. Saleh
- Department of Pathology, College of Medicine, University of Hail, Hail 55428, Saudi Arabia;
| | - Naief Dahran
- Department of Anatomy, Faculty of Medicine, University of Jeddah, Jeddah 21959, Saudi Arabia
| | - Alaa S. Alhegaili
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ahmad Salahuddin
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt (T.M.O.)
- Department of Biochemistry, College of Pharmacy, Al-Ayen Iraqi University, Nasiriyah 64001, Iraq
| | - Heba Abd-El-Azim
- Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt;
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Ahmed Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Tarek M. Okda
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt (T.M.O.)
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Gherman LM, Isachesku E, Zanoaga O, Braicu C, Berindan-Neagoe I. Molecular Markers in Canine Mammary Tumors. ACTA VET-BEOGRAD 2024; 74:159-182. [DOI: 10.2478/acve-2024-0012] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
Abstract
Canine mammary tumors (CMTs) are one of the most common neoplasms in female dogs. Unfortunately, the current diagnosis often occurs in later stages, and there is a pressing need for more comprehensive data on treatment options to improve overall prognosis. Consequently, the early detection of these tumors is critical for improving treatment outcomes and survival rates. As such, biomarkers are essential for improving the diagnosis, treatment, and prognosis of CMT, the reason for which further research is required to enhance our understanding of the disease. The most studied biomarkers for CMT are evaluated from serum and tissue samples using different molecular approaches and relate to proliferation and cell cycle. Several biomarkers were also described regarding cell damage, autophagy and apoptotic-related pathways, hypoxia, angiogenesis, EMT, invasion, metastasis or cancer stem features. Overall, biomarkers have shown the potential to be used as a tool for the early detection of mammary tumors in dogs. However, more research is needed to validate these biomarkers and to develop sensitive and specific diagnostic tests. In this regard, we aimed to review known biomarkers and their role in CMT comprehensively. We also encouraged further investigations of reliable biomarkers that could improve treatment outcomes and survival rates for dogs with this disease.
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Affiliation(s)
- Luciana-Mădălina Gherman
- University of Medicine and Pharmacy , Research Center of Functional Genomics, Biomedicine, and Translational Medicine Iuliu Hatieganu , Cluj-Napoca , Romania
- Animal Facility University of Medicine and Pharmacy Iuliu-Hatieganu , Cluj-Napoca , Romania
| | - Ekaterina Isachesku
- University of Medicine and Pharmacy , Research Center of Functional Genomics, Biomedicine, and Translational Medicine Iuliu Hatieganu , Cluj-Napoca , Romania
| | - Oana Zanoaga
- University of Medicine and Pharmacy , Research Center of Functional Genomics, Biomedicine, and Translational Medicine Iuliu Hatieganu , Cluj-Napoca , Romania
| | - Cornelia Braicu
- University of Medicine and Pharmacy , Research Center of Functional Genomics, Biomedicine, and Translational Medicine Iuliu Hatieganu , Cluj-Napoca , Romania
| | - Ioana Berindan-Neagoe
- University of Medicine and Pharmacy , Research Center of Functional Genomics, Biomedicine, and Translational Medicine Iuliu Hatieganu , Cluj-Napoca , Romania
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Chaudhry GES, Zeenia, Sharifi-Rad J, Calina D. Hispidulin: a promising anticancer agent and mechanistic breakthrough for targeted cancer therapy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1919-1934. [PMID: 37594522 DOI: 10.1007/s00210-023-02645-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 07/25/2023] [Indexed: 08/19/2023]
Abstract
Cancer is a complex disease characterized by dysregulated cell growth and division, posing significant challenges for effective treatment. Hispidulin, a flavonoid compound, has shown promising biological effects, particularly in the field of anticancer research. The main objective of this study is to investigate the anticancer properties of hispidulin and gain insight into its mechanistic targets in cancer cells. A comprehensive literature review was conducted to collect data on the anticancer effects of hispidulin. In vitro and in vivo studies were analyzed to identify the molecular targets and underlying mechanisms through which hispidulin exerts its anticancer activities. Hispidulin has shown significant effects on various aspects of cancer, including cell growth, proliferation, cell cycle regulation, angiogenesis, metastasis, and apoptosis. It has been observed to target both extrinsic and intrinsic apoptotic pathways, regulate cell cycle arrest, and modulate cancer progression pathways. The existing literature highlights the potential of hispidulin as a potent anticancer agent. Hispidulin exhibits promising potential as a therapeutic agent for cancer treatment. Its ability to induce apoptosis and modulate key molecular targets involved in cancer progression makes it a valuable candidate for further investigation. Additional pharmacological studies are needed to fully understand the specific targets and signaling pathways influenced by hispidulin in different types of cancer. Further research will contribute to the successful translation of hispidulin into clinical settings, allowing its utilization in conventional and advanced cancer therapies with improved therapeutic outcomes and reduced side effects.
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Affiliation(s)
- Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia.
| | - Zeenia
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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Hamed RA, Talib WH. Targeting cisplatin resistance in breast cancer using a combination of Thymoquinone and Silymarin: an in vitro and in vivo study. PHARMACIA 2024; 71:1-19. [DOI: 10.3897/pharmacia.71.e117997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Background: Breast cancer (BC) is considered the most diagnosed cancer among women globally. This is because of its high possibility of metastasis and high resistance to chemotherapy. Cisplatin is a platinum-based antitumor agent that is used to treat various types of cancer. However, the main obstacle to using this drug is drug resistance. Drug resistance is a cause of most relapses of cancer which eventually lead to death. Nowadays, combining natural products is a trend to overcome drug resistance. Thymoquinone (TQ) is a natural phytochemical that exists mainly in blackseed. It has been used in medicine for decades, especially as an anticancer agent. Silymarin is a milk thistle compound that exhibits anticancer, hepatoprotective, and neuroprotective activity. Hence, the combination of TQ and silymarin could be a probable solution to treat cancer and reduce chemoresistance.
Methods: This study tested this combination on cisplatin-sensitive (EMT6/P) and cisplatin-resistant (EMT6/CPR) mouse mammary cell lines. Apoptotic and antiproliferative activity was assessed for TQ and silymarin in vitro using caspase-3 and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assays, respectively. An in vivo study was performed to evaluate the effect of TQ and silymarin combination in mice inoculated with EMT6/P and EMT6/CPR cells. The safety profile was also examined using creatinine and liver enzyme assays.
Results: In vitro, the TQ and silymarin combination synergized in both cell lines. Also, this combination caused apoptosis induction at a higher rate than the single treatment in both cell lines. In vivo, TQ and silymarin combination resulted in a remarkable reduction in tumor size and enhanced the cure rate in mice implanted with EMT6/P and EMT6/CPR cell lines. According to the safety profile results, TQ and silymarin combination was safe.
Conclusion: In conclusion, the combination of TQ and silymarin provides a promising solution in treating BC resistant to cisplatin by inducing apoptosis. Further studies are needed to define the exact anticancer mechanisms of this combination.
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Pandit P, Shirke C, Bhatia N, Godad A, Belemkar S, Patel J, Zine S. An Overview of Recent Findings that Shed Light on the Connection between Fat and Cancer. Endocr Metab Immune Disord Drug Targets 2024; 24:178-193. [PMID: 37489790 DOI: 10.2174/1871530323666230724141942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/27/2023] [Accepted: 06/08/2023] [Indexed: 07/26/2023]
Abstract
Obesity and cancer have been found to have a direct link in epidemiological studies. Obesity raises the risk of cancer and associated chronic disorders. Furthermore, an imbalance of adipokines, like leptins, plays a crucial role in neoplasm pathogenesis, cell migration, and thereby, cancer metastasis. Also, leptin increases human epidermal growth factor receptor 2 (HER2) protein levels through the STAT3-mediated (signal transducer and activator of transcription) upregulation of heat shock protein (Hsp90) in breast cancer cells. It has been noticed that insulin and insulin-like growth factors (IGFs) act as mitosis activators in the host and cancerous breast epithelial cells. The condition of hyperinsulinemia explains the positive association between colorectal cancer and obesity. Furthermore, in prostate cancer, an alteration in sex hormone levels, testosterone and dihydrotestosterone, has been reported to occur, along with increased oxidative stress, which is the actual cause of the tumors. Whereas, there have been two interconnected factors that play a crucial role in the psychological cycle concerned with lung cancer. The review article focuses on all the prospects of etiological mechanisms that have found linkage with obesity and breast, colon, lung, and prostate cancers. Furthermore, the article has also highlighted how these new insights into the processes occur and, due to which reasons, obesity contributes to tumorigenesis. This review provides a detailed discussion on the progression, which can assist in the development of new and innovative techniques to interfere in this process, and it has been supported with insights based on evidence literature on approved clinical treatments for obesity and cancer.
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Affiliation(s)
- Parth Pandit
- Department of Pharmacology, University of Strathclyde, Glasgow, UK
| | - Chaitanya Shirke
- Department of Pharmaceutics, NMIMS Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management - (SPPSPTM), Mumbai, India
| | - Nirav Bhatia
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India
| | - Angel Godad
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India
| | - Sateesh Belemkar
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. M. Road, Vile Parle (W), Mumbai, India
| | - Jayshree Patel
- Department of Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India
| | - Sandip Zine
- Department of Pharmaceutical Chemistry, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India
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14
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Chen M, Qian C, Jin B, Hu C, Zhang L, Wang M, Zhou B, Zuo W, Huang L, Wang Y. Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma. Cancer Biol Ther 2023; 24:2162807. [PMID: 36647192 PMCID: PMC9851268 DOI: 10.1080/15384047.2022.2162807] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.
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Affiliation(s)
- Minxiao Chen
- Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China,Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Chenchen Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Bo Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Chenghong Hu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lingxi Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Minshan Wang
- Department of Pharmacy, the First Hospital of Xiangshan, Ningbo, China
| | - Bin Zhou
- Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Zuo
- Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Lijiang Huang
- Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China,Lijiang HuangThe Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China
| | - Yi Wang
- Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, China,Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China,CONTACT Yi Wang
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Hussain MS, Gupta G, Afzal M, Alqahtani SM, Samuel VP, Hassan Almalki W, Kazmi I, Alzarea SI, Saleem S, Dureja H, Singh SK, Dua K, Thangavelu L. Exploring the role of lncrna neat1 knockdown in regulating apoptosis across multiple cancer types: A review. Pathol Res Pract 2023; 252:154908. [PMID: 37950931 DOI: 10.1016/j.prp.2023.154908] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/22/2023] [Accepted: 10/24/2023] [Indexed: 11/13/2023]
Abstract
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression, contributing significantly to a diverse range of cellular processes, including apoptosis. One such lncRNA is NEAT1, which is elevated in several types of cancer and aid in cancer growth. However, recent studies have also demonstrated that the knockdown of NEAT1 can inhibit cancer cells proliferation, movement, and infiltration while enhancing apoptosis. This article explores the function of lncRNA NEAT1 knockdown in regulating apoptosis across multiple cancer types. We explore the existing understanding of NEAT1's involvement in the progression of malignant conditions, including its structure and functions. Additionally, we investigate the molecular mechanisms by which NEAT1 modulates the cell cycle, cellular proliferation, apoptosis, movement, and infiltration in diverse cancer types, including acute myeloid leukemia, breast cancer, cervical cancer, colorectal cancer, esophageal squamous cell carcinoma, glioma, non-small cell lung cancer, ovarian cancer, prostate cancer, and retinoblastoma. Furthermore, we review the recent studies investigating the therapeutic potential of NEAT1 knockdown in cancer treatment. Targeting the lncRNA NEAT1 presents a promising therapeutic approach for treating cancer. It has shown the ability to suppress cancer cell proliferation, migration, and invasion while promoting apoptosis in various cancer types.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017 Jaipur, Rajasthan, India
| | - Gaurav Gupta
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India; School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Safar M Alqahtani
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Vijaya Paul Samuel
- Department of Anatomy, RAK Medical & Health Sciences University, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah, United Arab Emirates
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Shakir Saleem
- Department of Public Health, College of Health Sciences, Saudi Electronic University, Riyadh, Saudi Arabia
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo NSW 2007, Australia
| | - Kamal Dua
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
| | - Lakshmi Thangavelu
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
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16
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Cao LL, Wu YK, Lin TX, Lin M, Chen YJ, Wang LQ, Wang JB, Lin JX, Lu J, Chen QY, Tu RH, Huang ZN, Lin JL, Zheng HL, Xie JW, Li P, Huang CM, Zheng CH. CDK5 promotes apoptosis and attenuates chemoresistance in gastric cancer via E2F1 signaling. Cancer Cell Int 2023; 23:286. [PMID: 37990321 PMCID: PMC10664659 DOI: 10.1186/s12935-023-03112-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 10/26/2023] [Indexed: 11/23/2023] Open
Abstract
BACKGROUND Chemoresistance is a major clinical challenge that leads to tumor metastasis and poor clinical outcome. The mechanisms underlying gastric cancer resistance to chemotherapy are still unclear. METHODS We conducted bioinformatics analyses of publicly available patient datasets to establish an apoptotic phenotype and determine the key pathways and clinical significance. In vitro cell models, in vivo mouse models, and numerous molecular assays, including western blotting, qRT-PCR, immunohistochemical staining, and coimmunoprecipitation assays were used to clarify the role of factors related to apoptosis in gastric cancer in this study. Differences between datasets were analyzed using the Student's t-test and two-way ANOVA; survival rates were estimated based on Kaplan-Meier analysis; and univariate and multivariate Cox proportional hazards models were used to evaluate prognostic factors. RESULTS Bulk transcriptomic analysis of gastric cancer samples established an apoptotic phenotype. Proapoptotic tumors were enriched for DNA repair and immune inflammatory signaling and associated with improved prognosis and chemotherapeutic benefits. Functionally, cyclin-dependent kinase 5 (CDK5) promoted apoptosis of gastric cancer cells and sensitized cells and mice to oxaliplatin. Mechanistically, we demonstrate that CDK5 stabilizes DP1 through direct binding to DP1 and subsequent activation of E2F1 signaling. Clinicopathological analysis indicated that CDK5 depletion correlated with poor prognosis and chemoresistance in human gastric tumors. CONCLUSION Our findings reveal that CDK5 promotes cell apoptosis by stabilizing DP1 and activating E2F1 signaling, suggesting its potential role in the prognosis and therapeutic decisions for patients with gastric cancer.
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Affiliation(s)
- Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Yu-Kai Wu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Tong-Xin Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Yu-Jing Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ling-Qian Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ze-Ning Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ju-Li Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Hua-Long Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
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Shen J, Xu Q, Chen L, Chang X, Shen R, Zhao Z, Zhu L, Wu Y, Hou X. Andrographolide inhibits infectious bronchitis virus-induced apoptosis, pyroptosis, and inflammation. Antivir Ther 2023; 28:13596535231207499. [PMID: 37846668 DOI: 10.1177/13596535231207499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
BACKGROUND Avian infectious bronchitis virus (IBV), a coronavirus, causes a huge economic loss to the poultry industry. Andrographolide (APL) is a compound with a variety of pharmacological properties, including antiviral and anti-inflammatory effects. In this study, APL was evaluated for antiviral activity by its anti-apoptotic, anti-pyroptosis, and anti-inflammatory effects. METHODS The cytotoxicity of APL was determined by the MTT method. We investigated the therapeutic impact of APL on IBV through a plate assay. We explored that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation in HD11 cells by RT-qPCR and immunofluorescence. Also, it was verified in the clinical chicken embryo trial. RESULTS We found that APL down-regulated apoptosis-related genes Caspase-3, Caspase-8, Caspase-9, Bax, Bid, and Bak, down-regulated pyroptosis gene DFNA5, and down-regulated inflammation-related genes (NF-κB, NLRP3, iNOS, TNF-α, and IL-1β). In addition, APL reduced the reactive oxygen species (ROS) production in cells. Finally, clinical trials showed that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation, as well as reduced the mortality and malformation of chicken embryos. CONCLUSIONS In this study, we delved into the antiviral properties of APL in the context of chicken macrophage (HD11) infection with IBV. Our findings confirm that andrographolide effectively inhibits apoptosis, pyroptosis, and inflammation by IBV infection. Furthermore, this inhibition was verified on chicken embryos in vivo. This inhibition suggests a substantial potential for APL as a therapeutic agent to mitigate the harmful effects of IBV on host cells.
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Affiliation(s)
- Jiachen Shen
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Qiuchi Xu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Lu Chen
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Xinyu Chang
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Ruiting Shen
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Zhenhua Zhao
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Lifei Zhu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Yifei Wu
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
| | - Xiaolin Hou
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing, China
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18
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Liu Y, Pei Z, Pan T, Wang H, Chen W, Lu W. Indole metabolites and colorectal cancer: Gut microbial tryptophan metabolism, host gut microbiome biomarkers, and potential intervention mechanisms. Microbiol Res 2023; 272:127392. [PMID: 37119643 DOI: 10.1016/j.micres.2023.127392] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 05/01/2023]
Abstract
Tryptophan (Trp) functions in host-disease interactions. Its metabolism is a multi-pathway process. Indole and its derivatives are Trp metabolites unique to the human gut microbiota. Changes in Trp metabolism have also been detected in colorectal cancer (CRC). Here, combined with the existing CRC biomarkers, we ascribed it to the altered bacteria having the indole-producing ability by making a genomic prediction. We also reviewed the anti-inflammatory and possible anti-cancer mechanisms of indoles, including their effects on tumor cells, the ability to repair the gut barrier, regulation of the host immune system, and provide resistance against oxidative stress. Indole and its derivatives, along with related bacteria, could be targeted as auxiliary strategies to restrain cancer development in the future.
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Affiliation(s)
- Yufei Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Zhangming Pei
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Tong Pan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Hongchao Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, PR China
| | - Wenwei Lu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; School of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China; National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, PR China.
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19
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Liu X, Hu Y, Xue Z, Zhang X, Liu X, Liu G, Wen M, Chen A, Huang B, Li X, Yang N, Wang J. Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway. J Transl Med 2023; 21:147. [PMID: 36829235 PMCID: PMC9960449 DOI: 10.1186/s12967-023-03984-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 02/13/2023] [Indexed: 02/26/2023] Open
Abstract
BACKGROUND Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. METHODS GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. RESULTS Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. CONCLUSIONS Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.
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Affiliation(s)
- Xuemeng Liu
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Yaotian Hu
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Zhiyi Xue
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Xun Zhang
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Xiaofei Liu
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Guowei Liu
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Muzi Wen
- grid.284723.80000 0000 8877 7471School of Public Health, Southern Medical University, Foushan, 528000 China
| | - Anjing Chen
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Bin Huang
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Xingang Li
- grid.452402.50000 0004 1808 3430Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012 China ,grid.27255.370000 0004 1761 1174Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117 China
| | - Ning Yang
- Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012, China. .,Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China. .,Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, 250012, China.
| | - Jian Wang
- Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, Jinan, 250012, China. .,Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250117, China. .,Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway.
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20
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Rausch WD, Fu S, Qin SL. Chinese herb formulae inhibit the proliferation of human colon cancer SW480 cells by inducing cell apoptosis. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2023. [DOI: 10.4103/2311-8571.369650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023] Open
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21
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Pandya N, Rani R, Kumar V, Kumar A. Discovery of potent Guanidine derivative that selectively binds and stabilizes the human BCL-2 G-quadruplex DNA and downregulates the transcription. Gene 2022; 851:146975. [PMID: 36261091 DOI: 10.1016/j.gene.2022.146975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/26/2022] [Accepted: 10/11/2022] [Indexed: 12/09/2022]
Abstract
Small molecules that interact with quadruplexes offer a wide range of potential applications, including not just as medications but also as sensors for quadruplexes structures. The BCL-2 is a proto-oncogene that often gets mutated in lethal cancer and could be an interesting target for developing an anti-cancer drug. In the present study, we have employed various biophysical techniques such as fluorescence, CD, Isothermal calorimeter, gel retardation, and PCR stop assay, indicating that Guanidine derivatives GD-1 and GD-2 selectively interact with high affinity with BCL-2 G-quadruplex over other G-quadruplex DNA and duplex DNA. The most promising small molecule GD-1 increases the thermostability of the BCL-2 GQ structure by 12°C. Our biological experiments such as ROS generation, qRT-PCR, western blot, TFP based Reporter assay, show that the GD-1 ligand causes a synthetic lethal interaction by suppressing the expression BCL-2 genes via interaction and stabilization of its the promoter G-quadruplexes in HeLa cells and act as a potential anti-cancer agent.
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Affiliation(s)
- Nirali Pandya
- Department for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, Simrol, India
| | - Reshma Rani
- Department of Biotechnology, Amity University, Noida
| | - Vinit Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research
| | - Amit Kumar
- Department for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, Simrol, India.
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22
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Lin TY, Wu TH, Tzou RD, Hsu YC, Lee KT, Tsai TH. Radix Glycyrrhizae Preparata Induces Cell Cycle Arrest and Induced Caspase-Dependent Apoptosis in Glioblastoma Multiforme. Neurol Int 2022; 14:804-823. [PMID: 36278690 PMCID: PMC9590052 DOI: 10.3390/neurolint14040066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/04/2022] [Accepted: 10/09/2022] [Indexed: 11/22/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive and devastating brain tumor characterized by poor prognosis and high rates of recurrence. Despite advances in multidisciplinary treatment, GBM constinues to have a poor overall survival. The Radix Glycyrrhizae Preparata (RGP) has been reported to possess anti-allergic, neuroprotective, antioxidative, and anti-inflammatory activities. However, it not clear what effect it may have on tumorigenesis in GBM. This study demonstrated that RGP reduced glioma cell viability and attenuated glioma cell locomotion in GBM8401 and U87MG cells. RGP treated cells had significant increase in the percentage of apoptotic cells and rise in the percentage of caspase-3 activity. In addition, the results of study's cell cycle analysis also showed that RGP arrested glioma cells at G2/M phase and Cell failure pass the G2 checkpoint by RGP treatment in GBM8401 Cells. Based on the above results, it seems to imply that RGP activated DNA damage checkpoint system and cell cycle regulators and induce apoptosis in established GBM cells. In conclusion, RGP can inhibit proliferation, cell locomotion, cell cycle progression and induce apoptosis in GBM cells in vitro.
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Affiliation(s)
- Tsung-Ying Lin
- Division of Neurosurgery, Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
| | - Tung-Hsuan Wu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan
| | - Rong-Dar Tzou
- Division of Neurosurgery, Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
| | - Yi-Chiang Hsu
- School of Medicine, I-Shou University, Kaohsiung 840, Taiwan
| | - Kuan-Ting Lee
- Division of Neurosurgery, Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
| | - Tai-Hsin Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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23
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Irfan M, Javed Z, Khan K, Khan N, Docea AO, Calina D, Sharifi-Rad J, Cho WC. Apoptosis evasion via long non-coding RNAs in colorectal cancer. Cancer Cell Int 2022; 22:280. [PMID: 36076273 PMCID: PMC9461221 DOI: 10.1186/s12935-022-02695-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/31/2022] [Indexed: 01/03/2023] Open
Abstract
Long non-coding RNA (LncRNA) is a novel and diverse class of regulatory transcripts that are frequently dysregulated in numerous tumor types. LncRNAs are involved in a complicated molecular network, regulating gene expression, and modulating diverse cellular activities in different cancers including colorectal cancer (CRC). Evidence indicates that lncRNAs can be used as a potential biomarker for the prognosis and diagnosis of CRC as they are aberrantly expressed in CRC cells. The high expression or silencing of lncRNAs is associated with cell proliferation, invasion, metastasis, chemoresistance and apoptosis in CRC. LncRNAs exert both pro-apoptotic and anti-apoptotic functions in CRC. The expression of some oncogene lncRNAs is upregulated which leads to the inhibition of apoptotic pathways, similarly, the tumor suppressor lncRNAs are downregulated in CRC. In this review, we describe the function and mechanisms of lncRNAs to regulate the expression of genes that are involved directly or indirectly in controlling cellular apoptosis in CRC. Furthermore, we also discussed the different apoptotic pathways in normal cells and the mechanisms by which CRC evade apoptosis.
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Affiliation(s)
- Muhammad Irfan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Khushbukhat Khan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Naila Khan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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24
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Lin CT, Lin CF, Wu JT, Tsai HP, Cheng SY, Liao HJ, Lin TC, Wu CH, Lin YC, Wang JH, Chang GR. Effects of Para-Toluenesulfonamide on Canine Melanoma Xenotransplants in a BALB/c Nude Mouse Model. Animals (Basel) 2022; 12:2272. [PMID: 36077992 PMCID: PMC9454485 DOI: 10.3390/ani12172272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
The pharmacological pathway of para-toluenesulfonamide (PTS) restricts the kinase activity of the mammalian target of rapamycin, potentially leading to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical effect on tumorigenesis. We aimed to examine the antitumor effect of PTS or PTS combined with cisplatin on canine melanoma implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. The mice were randomly divided into four groups: control, cisplatin, PTS, and PTS combined with cisplatin. Mice treated with PTS or PTS combined with cisplatin had retarded tumor growth and increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase phosphorylation, decreased inflammatory cytokine levels, reduced inflammation-related factors, enhanced anti-inflammation-related factors, and inhibition of metastasis-related factors. Mice treated with PTS combined with cisplatin exhibited significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with those treated with cisplatin or PTS alone. PTS or PTS combined with cisplatin could retard canine melanoma growth and inhibit tumorigenesis. PTS and cisplatin were found to have an obvious synergistic tumor-inhibiting effect on canine melanoma. PTS alone and PTS combined with cisplatin may be antitumor agents for canine melanoma treatment.
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Affiliation(s)
- Chien-Teng Lin
- Ph.D. Program of Agriculture Science, National Chiayi University, 300 University Road, Chiayi 60004, Taiwan
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Chuen-Fu Lin
- Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 912301, Taiwan
| | - Jui-Te Wu
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Hsiao-Pei Tsai
- Ph.D. Program of Agriculture Science, National Chiayi University, 300 University Road, Chiayi 60004, Taiwan
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Shu-Ying Cheng
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
- Department of Pet Medicine, Gongwin Biopharma Co., Ltd., 1 Section, 80 Jianguo North Road, Zhongshan District, Taipei 104001, Taiwan
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Chao-Hsuan Wu
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
- Department of Pet Medicine, Gongwin Biopharma Co., Ltd., 1 Section, 80 Jianguo North Road, Zhongshan District, Taipei 104001, Taiwan
| | - Yu-Chin Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
- Department of Pet Medicine, Gongwin Biopharma Co., Ltd., 1 Section, 80 Jianguo North Road, Zhongshan District, Taipei 104001, Taiwan
| | - Jiann-Hsiung Wang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
| | - Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan
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Chaudhry GES, Md Akim A, Sung YY, Sifzizul TMT. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Front Pharmacol 2022; 13:842376. [PMID: 36034846 PMCID: PMC9399632 DOI: 10.3389/fphar.2022.842376] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 07/13/2022] [Indexed: 11/24/2022] Open
Abstract
Cancer is a multifactorial, multi-stage disease, including complex cascades of signaling pathways—the cell growth governed by dysregulated and abrupt cell division. Due to the complexity and multi-regulatory cancer progression, cancer is still a challenging disease to treat and survive. The screening of extracts and fractions from plants and marine species might lead to the discovery of more effective compounds for cancer therapeutics. The isolated compounds and reformed analogs were known as future prospective contenders for anti-cancer chemotherapy. For example, Taxol, a potent mitotic inhibitor discovered from Taxus brevifolia, suppresses cell growth and arrest, induces apoptosis, and inhibits proliferation. Similarly, marine sponges show remarkable tumor chemo preventive and chemotherapeutic potential. However, there is limited research to date. Several plants and marine-derived anti-cancer compounds having the property to induce apoptosis have been approved for clinical trials. The anti-cancer activity kills the cell and slows the growth of cancer cells. Among cell death mechanisms, apoptosis induction is a more profound mechanism of cell death triggered by naturally isolated anti-cancer agents. Evading apoptosis is the major hurdle in killing cancer cells, a mechanism mainly regulated as intrinsic and extrinsic. However, it is possible to modify the apoptosis-resistant phenotype of the cell by altering many of these mechanisms. Various extracts and fractions successfully induce apoptosis, cell-cycle modulation, apoptosis, and anti-proliferative activity. Therefore, there is a pressing need to develop new anti-cancer drugs of natural origins to reduce the effects on normal cells. Here, we’ve emphasized the most critical elements: i) A better understanding of cancer progression and development and its origins, ii) Molecular strategies to inhibit the cell proliferation/Carcino-genesis, iii) Critical regulators of cancer cell proliferation and development, iv) Signaling Pathways in Apoptosis: Potential Targets for targeted therapeutics, v) Why Apoptosis induction is mandatory for effective chemotherapy, vi) Plants extracts/fractions as potential apoptotic inducers, vii) Marine extracts as Apoptotic inducers, viii) Marine isolated Targeted compounds as Apoptotic inducers (FDA Approved/treatment Phase). This study provides a potential therapeutic option for cancer, although more clinical studies are needed to verify its efficacy in cancer chemotherapy.
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Affiliation(s)
- Gul-e-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia
- *Correspondence: Gul-e-Saba Chaudhry, ,
| | - Abdah Md Akim
- Department of Biomedical Sciences, Faculty of Medicine and Health sciences, University of Putra Malaysia, Seri Kembangan, Malaysia
| | - Yeong Yik Sung
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Malaysia
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26
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Gómez‐Apo E, Silva‐Pereyra J, Soto‐Abraham V, Mondragón‐Maya A, Sanchez‐Lopez J. Immunohistochemical analysis of caspase expression in the brains of individuals with obesity or overweight. Obes Sci Pract 2022; 9:137-144. [PMID: 37034564 PMCID: PMC10073824 DOI: 10.1002/osp4.632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/03/2022] [Accepted: 07/26/2022] [Indexed: 11/10/2022] Open
Abstract
Mechanisms underlying the negative effects of obesity on the brain are still unknown. Obesity is associated with oxidative stress in the brain and neuroinflammation that promotes neurodegenerative diseases. Chronic low-grade neuroinflammation in obesity could be associated with lower volumes of gray matter and lower neuronal density. If neuroinflammation mediated by the expression of cytokines and chemokines leads to apoptosis, this can be assessed by examining caspase expression. The aim of this study was to compare the expression of caspases in the 16 brains of donors with obesity/overweight (n = 8; Body Mass Index [BMI] = 31.6 ± 4.35 kg/m2; 2 females; Age = 52.9 ± 4.76 years) and normal weight (n = 8; BMI = 21.8 ± 1.5 kg/m2; 3 females; Age = 37.8 ± 19.2 years). Sixteen human brain samples were processed. Serial paraffin sections were examined by anti-caspase immunochemistry (caspase-3, caspase-4, caspase-6, caspase-1, caspase-8, and caspase-9 antibodies). Postmortem samples of cerebral cortex tissue were captured as photomicrographs and the images obtained were analyzed using ImageJ software to obtain the percentage of positive caspase expression. Nonparametric Mann-Whitney U tests were performed to compare caspase expression between samples from donors with obesity/overweight and normal weight. Taking into consideration the immunohistochemistry results, the Search Tool for the Retrieval of Interacting Genes was used to model molecular interactions. Results showed that brain samples from individuals with obesity/overweight exhibited significantly greater values of positive expression for Caspase-1 (U = 16.5, p = 0.05, Cohen d = 0.89) and -8 (U = 15, p = 0.03, Cohen d = 0.99) than those from donors with normal weight. This study contributes to the knowledge about the inflammatory effects of obesity/overweight on brain, suggesting the activation of the alternative inflammasome pathway in which interact caspase-1 and -8.
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Affiliation(s)
- Erick Gómez‐Apo
- Servicio de Anatomía Patológica Hospital General de México “Dr. Eduardo Liceaga” Ciudad de México México
- Programa de Maestría y Doctorado en Ciencias Médicas y Odontológicas y de la Salud Universidad Nacional Autónoma de México Ciudad de México México
| | - Juan Silva‐Pereyra
- Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México Tlalnepantla Estado de México México
| | - Virgilia Soto‐Abraham
- Servicio de Anatomía Patológica Hospital General de México “Dr. Eduardo Liceaga” Ciudad de México México
| | - Alejandra Mondragón‐Maya
- Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México Tlalnepantla Estado de México México
| | - Javier Sanchez‐Lopez
- Escuela Nacional de Estudios Superiores Unidad Juriquilla Universidad Nacional Autónoma de México Querétaro Querétaro México
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27
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Antitumor Activity of Royal Jelly and Its Cellular Mechanisms against Ehrlich Solid Tumor in Mice. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7233997. [PMID: 35528154 PMCID: PMC9071879 DOI: 10.1155/2022/7233997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/23/2021] [Accepted: 03/18/2022] [Indexed: 12/24/2022]
Abstract
Objective The present study was aimed at evaluating the antitumor effects of royal jelly (RJ) obtained from Apis mellifera compared with cyclophosphamide against the Ehrlich solid tumors (EST) in mice. Methods Tumor growth inhibition, body weight, the serum level of alpha-fetoprotein (AFP) and carcinoembryonic antigen tumor (CAE), liver and kidney enzymes, tumor lipid peroxidation (LPO), nitric oxide (NO), antioxidant enzymes (glutathione peroxidase (GPx), catalase enzyme (CAT), and superoxide dismutase enzyme activity (SOD)), tumor necrosis factor alpha level (TNF-α), and the apoptosis-regulatory genes expression were assessed in EST mice treated with RJ (200 and 400 mg/kg orally once a day for 2 weeks). Results The results showed that treatment of EST-suffering mice with RJ at the doses of 200 and 400 mg/kg causes significant reduction in tumor volume and inhibition rate, body weight, tumor markers (AFP and CEA), serum level of liver and kidney, LPO and NO, TNF-α level, as well as the expression level of Bcl-2 in comparison with the EST mice receiving the normal saline; whereas RJ at the doses of 200 and 400 mg/kg/day significantly increased (p < 0.05) the level of antioxidant enzymes of GPx, CAT, and SOD and the expression level of caspase-3 and Bax genes. Conclusion The findings revealed that oral administration of royal jelly especially at the doses of 200 and 400 mg/kg exhibited promising antitumor effects against EST in mice through induction of apoptosis as well as its antioxidant and anti-inflammatory effects, which suggest it as a novel anticancer agent against tumor; however, additional surveys especially in clinical setting are necessary to approve these findings.
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He D, Ma Z, Xue K, Li H. Juxtamembrane 2 mimic peptide competitively inhibits mitochondrial trafficking and activates ROS-mediated apoptosis pathway to exert anti-tumor effects. Cell Death Dis 2022; 13:264. [PMID: 35332127 PMCID: PMC8948362 DOI: 10.1038/s41419-022-04639-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 11/26/2022]
Abstract
Our previous study demonstrates that a juxtamembrane 2 (JM2) mimic peptide can inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism remains unclear. In this study, JM2 is found to suppress the growth of 4T1 breast tumors by inducing apoptosis and inhibiting the proliferation of 4T1 tumor cells. Further study indicates that JM2 can stimulate the mitochondria to gather near the microtubule-organizing center of tumor cells and subsequently induce ROS-induced ROS release responses, which results in mitochondrial dysfunction and mitochondria-mediated apoptosis. In addition, JM2 can arrest cell cycle in S phase by regulating the expression of cell cycle-related proteins and consequently inhibit proliferation of tumor cells. Then, a previously designed JM2 grafted hyaluronic acid (HA) injectable hydrogel system (HA-JM2) is injected in a breast tumor-resected model and the HA-JM2 hydrogel can inhibit the malignant proliferation of residual tumor cells and suppress the breast tumor recurrence. These findings not only confirm the application potentials of JM2 in anti-tumor therapy and tumor post-surgery treatments but also provide greater understanding on the mechanisms by which JM2 inhibits tumor growth.
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Affiliation(s)
- Dan He
- School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China
| | - Zhijie Ma
- School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China
| | - Ke Xue
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai, 200011, China.
| | - Haiyan Li
- School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China.
- Chemical and Environmental Engineering, School of Engineering, RMIT University, 124 La Trobe Stø, Melbourne, VIC, 3000, Australia.
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Albalawi AE, Althobaiti NA, Alrdahe SS, Alhasani RH, Alaryani FS, BinMowyna MN. Anti-Tumor Effects of Queen Bee Acid (10-Hydroxy-2-Decenoic Acid) Alone and in Combination with Cyclophosphamide and Its Cellular Mechanisms against Ehrlich Solid Tumor in Mice. Molecules 2021; 26:molecules26227021. [PMID: 34834112 PMCID: PMC8617861 DOI: 10.3390/molecules26227021] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 01/08/2023] Open
Abstract
Queen bee acid or 10-hydroxy-2-decenoic acid (10-HDA) is one of the main and unique lipid components (fatty acids) in royal jelly. Previous studies have demonstrated that 10-HDA has various pharmacological and biological activities. The present study aims to evaluate the anti-tumor effects of 10-HDA alone and combined with cyclophosphamide (CP), as an alkylating agent which widely used for the treatment of neoplastic cancers, against the Ehrlich solid tumors (EST) in mice. Methods: A total of 72 female Swiss albino mice were divided into eight groups. EST mice were treated with 10-HDA (2.5 and 5 mg/kg) alone and combined with CP (25 mg/kg) orally once a day for 2 weeks. Tumor growth inhibition, body weight, the serum level of alpha-fetoprotein (AFP) and carcinoembryonic antigen tumor (CAE), liver and kidney enzymes, tumor lipid peroxidation (LPO) and nitric oxide (NO), antioxidant enzymes (e.g. glutathione reductase (GR), glutathione peroxidase (GPx), catalase enzyme (CAT)), tumor necrosis factor alpha level (TNF-α), and the apoptosis-regulatory genes expression were assessed in tested mice. Results: the findings exhibited that treatment of EST-suffering mice with 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) decreased the tumor volume and inhibition rate, tumor markers (AFP and CEA), serum level of liver and kidney, LPO and NO, TNF-α level, as well as the expression level of Bcl-2 in comparison with the mice in the C2 group; while 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) improved the level of antioxidant enzymes of GPx, CAT, and SOD and the expression level of caspase-3 and Bax genes. Conclusions: According to the results of the present investigations, 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP showed promising antitumor effects against EST in mice and can be recommended as a new or alternative anticancer agent against tumor; nevertheless, further investigations, particularly in clinical setting, are required to confirm these results.
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Affiliation(s)
- Aishah E. Albalawi
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
- Correspondence:
| | - Norah A. Althobaiti
- Department of Biology, College of Science and Humanities-Al Quwaiiyah, Shaqra University, Al Quwaiiyah 19257, Saudi Arabia;
| | - Salma Saleh Alrdahe
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Reem Hasaballah Alhasani
- Department of Biology, Faculty of Applied Science, Umm Al-Qura University, Makkah 21961, Saudi Arabia;
| | - Fatima S. Alaryani
- Department of Biology, Faculty of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia;
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Berger Fridman I, Kostas J, Gregus M, Ray S, Sullivan MR, Ivanov AR, Cohen S, Konry T. High-throughput microfluidic 3D biomimetic model enabling quantitative description of the human breast tumor microenvironment. Acta Biomater 2021; 132:473-488. [PMID: 34153511 PMCID: PMC8434998 DOI: 10.1016/j.actbio.2021.06.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/31/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022]
Abstract
Cancer is driven by both genetic aberrations in the tumor cells and fundamental changes in the tumor microenvironment (TME). These changes offer potential targets for novel therapeutics, yet lack of in vitro 3D models recapitulating this complex microenvironment impedes such progress. Here, we generated several tumor-stroma scaffolds reflecting the dynamic in vivo breast TME, using a high throughput microfluidic system. Alginate (Alg) or alginate-alginate sulfate (Alg/Alg-S) hydrogels were used as ECM-mimics, enabling the encapsulation and culture of tumor cells, fibroblasts and immune cells (macrophages and T cells, of the innate and adaptive immune systems, respectively). Specifically, Alg/Alg-S was shown capable of capturing and presenting growth factors and cytokines with binding affinity that is comparable to heparin. Viability and cytotoxicity were shown to strongly correlate with the dynamics of cellular milieu, as well as hydrogel type. Using on-chip immunofluorescence, production of reactive oxygen species and apoptosis were imaged and quantitatively analyzed. We then show how macrophages in our microfluidic system were shifted from a proinflammatory to an immunosuppressive phenotype when encapsulated in Alg/Alg-S, reflecting in vivo TME dynamics. LC-MS proteomic profiling of tumor cells sorted from the TME scaffolds revealed upregulation of proteins involved in cell-cell interactions and immunomodulation in Alg/Alg-S scaffolds, correlating with in vivo findings and demonstrating the appropriateness of Alg/Alg-S as an ECM biomimetic. Finally, we show the formation of large tumor-derived vesicles, formed exclusively in Alg/Alg-S scaffolds. Altogether, our system offers a robust platform for quantitative description of the breast TME that successfully recapitulates in vivo patterns. STATEMENT OF SIGNIFICANCE: Cancer progression is driven by profound changes in both tumor cells and surrounding stroma. Here, we present a high throughput microfluidic system for the generation and analysis of dynamic tumor-stroma scaffolds, that mimic the complex in vivo TME cell proportions and compositions, constructing robust in vitro models for the study of the TME. Utilizing Alg/Alg-S as a bioinspired ECM, mimicking heparin's in vivo capabilities of capturing and presenting signaling molecules, we show how Alg/Alg-S induces complex in vivo-like responses in our models. Alg/Alg-S is shown here to promote dynamic protein expression patterns, that can serve as potential therapeutic targets for breast cancer treatment. Formation of large tumor-derived vesicles, observed exclusively in the Alg/Alg-S scaffolds suggests a mechanism for tumor survival.
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Affiliation(s)
- Ilana Berger Fridman
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA; Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and Regenerative Medicine and Stem Cell Center, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel.
| | - James Kostas
- Department of Chemistry and Chemical Biology, Barnett Institute of Chemical and Biological Analysis, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
| | - Michal Gregus
- Department of Chemistry and Chemical Biology, Barnett Institute of Chemical and Biological Analysis, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
| | - Somak Ray
- Department of Chemistry and Chemical Biology, Barnett Institute of Chemical and Biological Analysis, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
| | - Matthew R Sullivan
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
| | - Alexander R Ivanov
- Department of Chemistry and Chemical Biology, Barnett Institute of Chemical and Biological Analysis, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
| | - Smadar Cohen
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and Regenerative Medicine and Stem Cell Center, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel.
| | - Tania Konry
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
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Tawfik MM, Eissa N, Althobaiti F, Fayad E, Abu Almaaty AH. Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells. Molecules 2021; 26:molecules26175185. [PMID: 34500621 PMCID: PMC8434601 DOI: 10.3390/molecules26175185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 12/18/2022] Open
Abstract
Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors' knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.
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Affiliation(s)
- Mohamed M. Tawfik
- Department of Zoology, Faculty of Science, Port Said University, Port Said 42526, Egypt; (N.E.); (A.H.A.A.)
- Correspondence: (M.M.T.); (E.F.)
| | - Nourhan Eissa
- Department of Zoology, Faculty of Science, Port Said University, Port Said 42526, Egypt; (N.E.); (A.H.A.A.)
| | - Fayez Althobaiti
- Department of Biotechnology, Faculty of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Eman Fayad
- Department of Biotechnology, Faculty of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
- Correspondence: (M.M.T.); (E.F.)
| | - Ali H. Abu Almaaty
- Department of Zoology, Faculty of Science, Port Said University, Port Said 42526, Egypt; (N.E.); (A.H.A.A.)
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Lee HS, Park BS, Kang HM, Kim JH, Shin SH, Kim IR. Role of Luteolin-Induced Apoptosis and Autophagy in Human Glioblastoma Cell Lines. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:879. [PMID: 34577802 PMCID: PMC8470580 DOI: 10.3390/medicina57090879] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 01/07/2023]
Abstract
Background and Objectives: Malignant glioblastoma (GBM) is caused by abnormal proliferation of glial cells, which are found in the brain. The therapeutic effects of surgical treatment, radiation therapy, and chemo-therapy against GBM are relatively poor compared with their effects against other tumors. Luteolin is abundant in peanut shells and is also found in herbs and other plants, such as thyme, green pepper, and celery. Luteolin is known to be effective against obesity and metabolic syndrome. The anti-inflammatory, and anti-cancer activities of luteolin have been investigated. Most studies have focused on the antioxidant and anti-inflammatory effects of luteolin, which is a natural flavonoid. However, the association between the induction of apoptosis by luteolin in GBM and autophagy has not yet been investigated. This study thus aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship. Materials and Methods: A172 and U-373MG glioblastoma cell lines were used for this experiment. We confirmed the apoptosis effect of Luteolin on GBM cells using methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence, Flow cytometry (FACS) western blot, and real-time quantitative PCR (qPCR). Results: In the luteolin-treated A172 and U-373MG cells, cell viability decreased in a concentration- and time-dependent manner. In addition, in A172 and U-373MG cells treated with luteolin at concentrations greater than 100 μM, nuclear fragmentation, which is a typical morphological change characterizing apoptosis, as well as fragmentation of caspase-3 and Poly (ADP-ribose) polymerase (PARP), which are apoptosis-related factors, were observed. Autophagy was induced after treatment with at least 50 μM luteolin. Inhibition of autophagy using 3MA allowed for a low concentration of luteolin to more effectively induce apoptosis in A172 and U-373MG cells. Conclusions: Results showed that luteolin induces apoptosis and autophagy and that the luteolin-induced autophagy promotes cell survival. Therefore, an appropriate combination therapy involving luteolin and an autophagy inhibitor is expected to improve the prognosis of GBM treatment.
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Affiliation(s)
- Hye-Sung Lee
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan-si 50612, Korea; (H.-S.L.); (S.-H.S.)
| | - Bong-Soo Park
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, 49, Mulguem-eup, Yangsan-si 50612, Korea; (B.-S.P.); (H.-M.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan-si 50612, Korea
| | - Hae-Mi Kang
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, 49, Mulguem-eup, Yangsan-si 50612, Korea; (B.-S.P.); (H.-M.K.)
| | - Jung-Han Kim
- Medical Center, Department of Oral and Maxillofacial Surgery, Dong-A University, 26, Daesingongwon-ro, Seo-gu, Busan 49201, Korea;
| | - Sang-Hun Shin
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan-si 50612, Korea; (H.-S.L.); (S.-H.S.)
| | - In-Ryoung Kim
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Busandaehak-ro, 49, Mulguem-eup, Yangsan-si 50612, Korea; (B.-S.P.); (H.-M.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan-si 50612, Korea
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Chang GR, Kuo CY, Tsai MY, Lin WL, Lin TC, Liao HJ, Chen CH, Wang YC. Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice. Molecules 2021; 26:molecules26154683. [PMID: 34361836 PMCID: PMC8347948 DOI: 10.3390/molecules26154683] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 01/05/2023] Open
Abstract
Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1β, TNF-α, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (T.-C.L.); (H.-J.L.)
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289 Jianguo Road, Xindian District, New Taipei 231405, Taiwan;
- Department of Nursing, Cardinal Tien College of Healthcare and Management, 112 Minzu Road, Sindian District, New Taipei 231038, Taiwan
| | - Ming-Yang Tsai
- Animal Industry Division, Livestock Research Institute, Council of Agriculture, Executive Yuan, 112 Muchang, Xinhua Dist, Tainan 71246, Taiwan;
- Graduate Institute of Bioresources, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 91201, Taiwan
| | - Wei-Li Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan;
- General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (T.-C.L.); (H.-J.L.)
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (T.-C.L.); (H.-J.L.)
| | - Chung-Hung Chen
- Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 505029, Taiwan
- Correspondence: (C.-H.C.); (Y.-C.W.); Tel.: +886-975-617357 (C.-H.C.); +886-2332-3456 (Y.-C.W.)
| | - Yu-Chen Wang
- Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 413505, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 413305, Taiwan
- Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan
- College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan
- Correspondence: (C.-H.C.); (Y.-C.W.); Tel.: +886-975-617357 (C.-H.C.); +886-2332-3456 (Y.-C.W.)
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Lee JY, Lim HM, Lee CM, Park SH, Nam MJ. Indole-3-carbinol inhibits the proliferation of colorectal carcinoma LoVo cells through activation of the apoptotic signaling pathway. Hum Exp Toxicol 2021; 40:2099-2112. [PMID: 34085558 DOI: 10.1177/09603271211021475] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Indole-3-carbinol (I3C) is a phytochemical that exhibits growth-inhibitory activity against various cancer cells. However, there are limited studies on the effects of I3C on colon cancer cells. In this study, the growth-inhibitory activity of I3C against the human colorectal carcinoma cell line (LoVo) was examined. The results of the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, colony formation, and cell counting assays revealed that I3C suppressed the proliferation of LoVo cells. Microscopy and wound-healing analyses revealed that I3C affected the morphology and inhibited the migration of LoVo cells, respectively. I3C induced apoptosis and DNA fragmentation as evidenced by the results of fluorescein isothiocyanate-conjugated annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay, respectively. Additionally, I3C arrested the cell cycle at the G0/G1 phase and enhanced the reactive oxygen species levels. Western blotting analysis revealed that treatment with I3C resulted in the activation of apoptotic proteins, such as poly(ADP-ribose) polymerase, caspase-3, caspase-7, caspase-9, Bax, Bim, and p53 in LoVo cells. These results indicate that I3C induces apoptosis in LoVo cells by upregulating p53, leading to the activation of Bax and caspases. Taken together, I3C exerts cytotoxic effects on LoVo cells by activating apoptosis.
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Affiliation(s)
- J Y Lee
- Department of Biological Science, 65440Gachon University, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - H M Lim
- Department of Biological Science, 65440Gachon University, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - C M Lee
- Department of Bio&Chemical Engineering, 65686Hongik University, Jochiwon-eup, Sejong-si, Republic of Korea
| | - S-H Park
- Department of Bio&Chemical Engineering, 65686Hongik University, Jochiwon-eup, Sejong-si, Republic of Korea
| | - M J Nam
- Department of Biological Science, 65440Gachon University, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
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Imani A, Maleki N, Bohlouli S, Kouhsoltani M, Sharifi S, Maleki Dizaj S. Molecular mechanisms of anticancer effect of rutin. Phytother Res 2021; 35:2500-2513. [PMID: 33295678 DOI: 10.1002/ptr.6977] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 10/13/2020] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Because of the extensive biological functions of natural substances such as bioflavonoids, and their high safety and low costs, they could have high priority application in the health care system. The antioxidant properties of rutin, a polyphenolic bioflavonoid, have been well documented and demonstrated a wide range of pharmacological applications in cancer research. Since chemotherapeutic drugs have a wide range of side effects and rutin is a safe anticancer agent with minor side effects so recent investigations are performed for study of mechanisms of its anticancer effect. Both in-vivo and in-vitro examinations on anticancer mechanisms of this natural agent have been widely carried out. Regulation of different cellular signaling pathways such as Wnt/β-catenin, p53-independent pathway, PI3K/Akt, JAK/STAT, MAPK, p53, apoptosis as well as NF-ĸB signaling pathways helps to mediate the anticancer impacts of this agent. This study tried to review the molecular mechanisms of rutin anticancer effect on various types of cancer. Deep exploration of these anticancer mechanisms can facilitate the development of this beneficial compound for its application in the treatment of different cancers.
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Affiliation(s)
- Amir Imani
- Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasim Maleki
- Department of Prosthodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Bohlouli
- Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Kouhsoltani
- Oral and Maxillofacial Department of Pathology, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Zhao X, Zhang N, Huang Y, Dou X, Peng X, Wang W, Zhang Z, Wang R, Qiu Y, Jin M, Kong D. Lansoprazole Alone or in Combination With Gefitinib Shows Antitumor Activity Against Non-small Cell Lung Cancer A549 Cells in vitro and in vivo. Front Cell Dev Biol 2021; 9:655559. [PMID: 33959611 PMCID: PMC8093516 DOI: 10.3389/fcell.2021.655559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
Lansoprazole (Lpz) is an FDA-approved proton pump inhibitor (PPI) drug for the therapy of acid-related diseases. Aiming to explore the new application of old drugs, we recently investigated the antitumor effect of Lpz. We demonstrated that the PPI Lpz played a tumor suppressive role in non-small cell lung cancer (NSCLC) A549 cells. Mechanistically, Lpz induced apoptosis and G0/G1 cell cycle arrest by inhibiting the activation of signal transducer and activator of transcription (Stat) 3 and the phosphoinositide 3-kinase (PI3K)/Akt and Raf/ERK pathways. In addition, Lpz inhibited autophagy by blocking the fusion of autophagosomes with lysosomes. Furthermore, Lpz in combination with gefitinib (Gef) showed a synergistic antitumor effect on A549 cells, with enhanced G0/G1 cell cycle arrest and apoptosis. The combination inhibited Stat3 phosphorylation, PI3K/Akt and Raf/ERK signaling, affecting cell cycle-related proteins such as p-Rb, cyclin D1 and p27, as well as apoptotic proteins such as Bax, Bcl-2, caspase-3, and poly (ADP-ribose) polymerase (PARP). In vivo, coadministration with Lpz and Gef significantly attenuated the growth of A549 nude mouse xenograft models. These findings suggest that Lpz might be applied in combination with Gef for NSCLC therapy, but further evidence is required.
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Affiliation(s)
- Xiaoxia Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Ning Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yingying Huang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xiaojing Dou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xiaolin Peng
- Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China
| | - Wei Wang
- Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Ran Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Meihua Jin
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.,School of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, China
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Rachakhom W, Banjerdpongchai R. Effect of Calomelanone, a Dihydrochalcone Analogue, on Human Cancer Apoptosis/Regulated Cell Death in an In Vitro Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4926821. [PMID: 33415148 PMCID: PMC7769633 DOI: 10.1155/2020/4926821] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/24/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022]
Abstract
Calomelanone, 2',6'-dihydroxy-4,4'-dimethoxydihydrochalcone, possesses anticancer activities. This study was conducted to investigate the cytotoxic effect of calomelanone, a dihydrochalcone analogue, on human cancer cells and its associated mechanisms. The cytotoxic effect of calomelanone was measured by MTT assay. Annexin V-FITC/propidium iodide and DiOC6 staining that employed flow cytometry were used to determine the mode of cell death and reduction of mitochondrial transmembrane potential (MTP), respectively. Caspase activities were measured using specific substrates and colorimetric analysis. The expression levels of Bcl-2 family proteins were determined by immunoblotting. Reactive oxygen species were also measured using 2',7'-dihydrodichlorofluorescein diacetate and dihydroethidium (fluorescence dyes). Calomelanone was found to be toxic towards various human cancer cells, including acute promyelocytic HL-60 and monocytic leukemic U937 cells, in a dose-dependent manner at 24 h and human hepatocellular HepG2 cells at 48 h. However, the proliferation of HepG2 cells increased at 24 h. Calomelanone was found to induce apoptosis in HL-60 and U937 at 24 h and HepG2 apoptosis at 48 h via the intrinsic pathway by inducing MTP disruption. This compound also induced caspase-3, caspase-8, and caspase-9 activities. Calomelanone upregulated proapoptotic Bax and Bak and downregulated antiapoptotic Bcl-xL proteins in HepG2 cells. Moreover, signaling was also associated with oxidative stress in HepG2 cells. Calomelanone induced autophagy at 24 h of treatment, which was evidenced by staining with monodansylcadaverine (MDC) to represent autophagic flux. This was associated with a decrease of Akt (survival pathway) and an upregulation of Atg5 (the marker of autophagy). Thus, calomelanone induced apoptosis/regulated cell death in HL-60, U937, and HepG2 cells. However, it also induced autophagy in HepG2 depending on duration, dose, and type of cells. Thus, calomelanone could be used as a potential anticancer agent for cancer treatment. Nevertheless, acute and chronic toxicity should be further investigated in animals before conducting investigations in human patients.
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Affiliation(s)
- Wasitta Rachakhom
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Ratana Banjerdpongchai
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
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Yoon JH, Shin JW, Pham TH, Choi YJ, Ryu HW, Oh SR, Oh JW, Yoon DY. Methyl lucidone induces apoptosis and G 2/M phase arrest via the PI3K/Akt/NF-κB pathway in ovarian cancer cells. PHARMACEUTICAL BIOLOGY 2020; 58:51-59. [PMID: 31875458 PMCID: PMC6968553 DOI: 10.1080/13880209.2019.1701044] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Context: Methyl lucidone (ML) from the dried fruit of Lindera erythrocarpa Makino (Lauraceae) exhibits cytotoxic effects in various cancer cell lines. However, its effects on ovarian cancer cells remain unknown.Objective: This study evaluates the mechanism of ML-induced apoptosis, cell cycle distribution in ovarian cells.Materials and methods: The cytotoxic effect of ML (2.5-80 µM) on OVCAR-8 and SKOV-3 cells was evaluated by MTS assay for 24 and 48 h. Apoptosis and cell cycle arrest were analysed by flow cytometry. PCR, western blot analyses were performed to examine the related signalling pathways.Results: ML induced significant cellular morphological changes and apoptosis in ovarian cancer cells, leading to an antiproliferative effect (IC50 = 33.3-54.7 µM for OVCAR-8 and 48.8-60.7 µM for SKOV-3 cells). Treatment with ML induced cleavage of caspase-3/9 and PARP and release of cytochrome c from the mitochondria. Moreover, ML downregulated the expression of Bcl-2 and Bcl-xL and induced cell cycle arrest in the G2/M phase. Additionally, ML suppressed the expression of cyclin-A/B and promoted that of the cyclin-dependent kinase inhibitors p21 and p27. The expression of death receptors was not altered. Interestingly, ML also inhibited the activity of PI3K/Akt and NF-κB.Discussion and conclusions: ML caused G2/M phase arrest and apoptosis in ovarian cancer cells by activating intrinsic apoptotic pathways and suppressing the PI3K/Akt survival pathway. ML may be a potential anticancer agent to suppress ovarian cancer proliferation; thus, to improve the survival rate of cancer patients.
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Affiliation(s)
- Jae-Hwan Yoon
- Department of Bioscience and Biotechnology, Research Institute of Bioactive-Metabolome Network, Konkuk University, Seoul, Republic of Korea
| | - Jong-Woon Shin
- Department of Bioscience and Biotechnology, Research Institute of Bioactive-Metabolome Network, Konkuk University, Seoul, Republic of Korea
| | - Thu-Huyen Pham
- Department of Bioscience and Biotechnology, Research Institute of Bioactive-Metabolome Network, Konkuk University, Seoul, Republic of Korea
| | - Youn-Jin Choi
- Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung-Won Ryu
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungcheungbuk-do, Republic of Korea
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungcheungbuk-do, Republic of Korea
| | - Jae-Wook Oh
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Research Institute of Bioactive-Metabolome Network, Konkuk University, Seoul, Republic of Korea
- CONTACT Do-Young Yoon Department of Bioscience and Biotechnology, Research Institute of Bioactive-Metabolome Network, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul05029, Republic of Korea
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Li Y, Zhang J, Liu YD, Zhou XY, Chen X, Zhe J, Zhang QY, Zhang XF, Chen YX, Wang Z, Chen SL. Long non-coding RNA TUG1 and its molecular mechanisms in polycystic ovary syndrome. RNA Biol 2020; 17:1798-1810. [PMID: 32559120 PMCID: PMC7714456 DOI: 10.1080/15476286.2020.1783850] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/26/2020] [Accepted: 06/12/2020] [Indexed: 02/09/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) causes anovulatory infertility in women of reproductive age, but etiopathogenesis of PCOS remains undetermined. Taurine up-regulated 1 (TUG1), an evolutionarily conserved long non-coding RNA, performs various biological functions; however, the role of TUG1 in PCOS remains unclear. Herein, TUG1 expression was assayed in granulosa cells (GCs) of 100 patients with PCOS and 100 control participants. Receiver operating characteristic (ROC) curve analysis was conducted to determine the diagnostic value of TUG1 in PCOS. TUG1 expression was also silenced in KGN cells to explore the role of TUG1 in cellular proliferation, apoptosis, cell-cycle progression, autophagy, and steroidogenesis. We found that TUG1 levels were dramatically increased in the PCOS group compared with those of the control group; this increased expression was related to a rising antral follicle count (R = 0.209, P < 0.001 versus control). The ROC curve indicated a significant separation between PCOS group and the control group (AUC: 0.702; 95% CI: 0.630-0.773; P < 0.001). TUG1 showed a predominantly nuclear localization in human GCs. TUG1 knockdown reduced cellular proliferation, and promoted MAPKs pathway-dependent apoptosis and P21-dependent autophagy, but may not affect cell-cycle progression. TUG1 knockdown increased aromatase expression and oestradiol biosynthesis. Our results indicate that increased TUG1 expression in PCOS GCs may contribute to excessive follicular activation and growth, and may disrupt the selection of dominant follicle. Our study shows that TUG1 can be used as a diagnostic biomarker for PCOS.
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Affiliation(s)
- Ying Li
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jun Zhang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yu-Dong Liu
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xing-Yu Zhou
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xin Chen
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jing Zhe
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Qing-Yan Zhang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xiao-Fei Zhang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Ying-Xue Chen
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Zhe Wang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shi-Ling Chen
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
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Gu W, Wen K, Yan C, Li S, Liu T, Xu C, Liu L, Zhao M, Zhang J, Geng T, Gong D. Maintaining intestinal structural integrity is a potential protective mechanism against inflammation in goose fatty liver. Poult Sci 2020; 99:5297-5307. [PMID: 33142445 PMCID: PMC7647926 DOI: 10.1016/j.psj.2020.08.052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 07/21/2020] [Accepted: 08/10/2020] [Indexed: 12/23/2022] Open
Abstract
Overfeeding causes severe steatosis but not inflammation in goose liver, suggesting existence of protective components. Previous studies have shown that some intestinal microbes and their metabolites damage intestinal structural integrity and function, thus causing inflammation in the development of human and mouse nonalcoholic fatty liver disease. Therefore, this study hypothesizes that intestinal structural integrity of goose is maintained during overfeeding, which may provide goose fatty liver a protective mechanism against inflammation. To test this hypothesis, 48 seventy-day-old healthy Landes male geese were overfed (as overfeeding group) or normally fed (as control group). Blood and intestine (jejunum, ileum, and cecum) samples were harvested on the 12th and 24th d of overfeeding. Data showed that goose fatty liver was successfully induced by 24 d of overfeeding. Hematoxylin-eosin staining analysis indicated that the arrangement of villi and crypts in the intestine was orderly, and the intestinal structure was intact with no pathological symptoms in the 2 groups. Enzyme-linked immunosorbent assay and quantitative PCR analysis indicated no significant differences in the expression of tight junction and inflammation-related genes as well as plasma lipopolysaccharide concentration between the groups. Ileal hypertrophy and cecal atrophy were observed in the overfed vs. control geese, probably because of change of sphingolipid metabolism. Activation of apoptotic pathway may help cecum avoid necrosis-induced inflammation. In conclusion, healthy and intact intestine provides a layer of protection for goose fatty liver against inflammation. Sphingolipid metabolism may be involved in the adaptation of ileum and cecum to overfeeding. The hypertrophy of ileum makes it an important contributor to the development of goose fatty liver. The atrophy and decline in the function of cecum may be caused by apoptosis induced by overfeeding.
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Affiliation(s)
- Wang Gu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Kang Wen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Chunchi Yan
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Shuo Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Tongjun Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Cheng Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Minmeng Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Jun Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China
| | - Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China.
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu Province 225009, P. R. China.
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Heidari Z, Eskandari M, Aryan A, Rostamzad F, Salimi S. The effect of CASP3 rs4647610 and rs4647602 polymorphisms on tumour size and cancer stage in papillary thyroid carcinoma. Br J Biomed Sci 2020; 77:129-134. [PMID: 32151194 DOI: 10.1080/09674845.2020.1741249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer whose incidence has increased in recent years. Dysregulated apoptosis is known in the pathogenesis of various cancers. Caspase-3 is an important apoptotic component and its abnormal function may play a key role in cancer pathogenesis. We tested the hypothesis of a link between CASP3 single nucleotide polymorphisms rs4647610 and rs4647602 on PTC and its clinical outcomes. MATERIAL AND METHODS A total of 134 PTC patients and 151 healthy controls were genotyped for CASP3 rs4647610 and rs4647602 single nucleotide polymorphisms (SNPs) using PCR-RFLP method. RESULTS Allele and genotype frequencies of both SNPs were not different between cases and controls. The combined genotypes and haplotypes were not linked to PTC. However, the frequencies of CASP3 rs4647610 GA and AA genotypes were higher in PTC patients with larger tumour size (≥1 cm), and the rs4647610 SNP was associated with increased tumour size in the dominant model (OR 3.4 [95% CI, 1.1-11], P = 0.04). The CASP3 rs4647602CA and AA genotypes were higher in PTC patients with lower TNM stage (I-II) compared to higher stages (III-IV). No association was observed between CASP3 polymorphisms and other PTC outcomes. CONCLUSION Although CASP3 rs4647610 and rs4647602 SNPs are not associated with PTC, rs4647610 is linked to larger tumour size, and rs4647602 to lower stage of cancer.
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Affiliation(s)
- Z Heidari
- Department of Internal Medicine, Zahedan University of Medical Sciences , Zahedan, Iran
| | - M Eskandari
- Department of Laboratory Sciences, Zahedan University of Medical Sciences , Zahedan, Iran
| | - A Aryan
- Radiology Department, Zahedan University of Medical Sciences , Zahedan, Iran
| | - F Rostamzad
- Department of Biology, Faculty of Science, Islamic Azad University , Marand, Iran
| | - S Salimi
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences , Zahedan, Iran.,Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences , Zahedan, Iran
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Induction of Apoptosis by Gluconasturtiin-Isothiocyanate (GNST-ITC) in Human Hepatocarcinoma HepG2 Cells and Human Breast Adenocarcinoma MCF-7 Cells. Molecules 2020; 25:molecules25051240. [PMID: 32182965 PMCID: PMC7179403 DOI: 10.3390/molecules25051240] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 01/26/2023] Open
Abstract
Gluconasturtiin, a glucosinolate present in watercress, is hydrolysed by myrosinase to form gluconasturtiin-isothiocyanate (GNST-ITC), which has potential chemopreventive effects; however, the underlying mechanisms of action have not been explored, mainly in human cell lines. The purpose of the study is to evaluate the cytotoxicity of GNST-ITC and to further assess its potential to induce apoptosis. GNST-ITC inhibited cell proliferation in both human hepatocarcinoma (HepG2) and human breast adenocarcinoma (MCF-7) cells with IC50 values of 7.83 µM and 5.02 µM, respectively. Morphological changes as a result of GNST-ITC-induced apoptosis showed chromatin condensation, nuclear fragmentation, and membrane blebbing. Additionally, Annexin V assay showed proportion of cells in early and late apoptosis upon exposure to GNST-ITC in a time-dependent manner. To delineate the mechanism of apoptosis, cell cycle arrest and expression of caspases were studied. GNST-ITC induced a time-dependent G2/M phase arrest, with reduction of 82% and 93% in HepG2 and MCF-7 cell lines, respectively. The same treatment also led to the subsequent expression of caspase-3/7 and -9 in both cells demonstrating mitochondrial-associated cell death. Collectively, these results reveal that GNST-ITC can inhibit cell proliferation and can induce cell death in HepG2 and MCF-7 cancer cells via apoptosis, highlighting its potential development as an anticancer agent.
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Dihydrochalcone Derivative Induces Breast Cancer Cell Apoptosis via Intrinsic, Extrinsic, and ER Stress Pathways but Abolishes EGFR/MAPK Pathway. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7298539. [PMID: 31772936 PMCID: PMC6855007 DOI: 10.1155/2019/7298539] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 08/07/2019] [Accepted: 08/25/2019] [Indexed: 12/24/2022]
Abstract
Dihydrochalcone derivatives are active compounds that have been purified from the Thai medicinal plant Cyathostemma argenteum. The objectives of this study were to investigate the effects of two dihydrochalcone derivatives on human breast cancer MDA-MB-231 and MCF-7 cell proliferation and to study the relevant mechanisms involved. The two dihydrochalcone derivatives are 4′,6′-dihydroxy-2′,4-dimethoxy-5′-(2″-hydroxybenzyl)dihydrochalcone (compound 1) and calomelanone (2′,6′-dihydroxy-4,4′-dimethoxydihydrochalcone, compound 2), both of which induced cytotoxicity toward both cell lines in a dose-dependent manner by using MTT assay. Treatment with both derivatives induced apoptosis as determined by annexin V-FITC/propidium iodide employing flow cytometry. The reduction of mitochondrial transmembrane potential (staining with 3,3′-dihexyloxacarbocyanine iodide, DiOC6, employing a flow cytometer) was established in the compound 1-treated cells. Compound 1 induced caspase-3, caspase-8, and caspase-9 activities in both cell lines, as has been determined by specific colorimetric substrates and a spectrophotometric microplate reader which indicated the involvement of both the extrinsic and intrinsic pathways. Calcium ion levels in mitochondrial and cytosolic compartments increased in compound 1-treated cells as detected by Rhod-2AM and Fluo-3AM intensity, respectively, indicating the involvement of the endoplasmic reticulum (ER) stress pathway. Compound 1 induced cell cycle arrest via enhanced atm and atr expressions and by upregulating proapoptotic proteins, namely, Bim, Bad, and tBid. Moreover, compound 1 significantly inhibited the EGFR/MAPK signaling pathway. In conclusion, compound 1 induced MDA-MB-231 and MCF-7 cell apoptosis via intrinsic, extrinsic, and ER stress pathways, whereas it ameliorated the EGFR/MAPK pathway in the MCF-7 cell line. Consequently, it is believed that compound 1 could be effectively developed for cancer treatments.
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Roque Marques KM, do Desterro MR, de Arruda SM, de Araújo Neto LN, do Carmo Alves de Lima M, de Almeida SMV, da Silva ECD, de Aquino TM, da Silva-Júnior EF, de Araújo-Júnior JX, de M Silva M, de A Dantas MD, Santos JCC, Figueiredo IM, Bazin MA, Marchand P, da Silva TG, Mendonça Junior FJB. 5-Nitro-Thiophene-Thiosemicarbazone Derivatives Present Antitumor Activity Mediated by Apoptosis and DNA Intercalation. Curr Top Med Chem 2019; 19:1075-1091. [PMID: 31223089 DOI: 10.2174/1568026619666190621120304] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 03/12/2019] [Accepted: 04/02/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.
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Affiliation(s)
- Karla Mirella Roque Marques
- Bioactive Products Prospecting Laboratory, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
| | - Maria Rodrigues do Desterro
- Bioactive Products Prospecting Laboratory, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
| | - Sandrine Maria de Arruda
- Bioactive Products Prospecting Laboratory, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
| | - Luiz Nascimento de Araújo Neto
- Laboratory of Chemistry and Therapeutic Innovation, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
| | - Maria do Carmo Alves de Lima
- Laboratory of Chemistry and Therapeutic Innovation, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
| | | | - Edjan Carlos Dantas da Silva
- Laboratory of Medicinal Chemistry, Nursing and Pharmacy School, Federal University of Alagoas, Maceio-AL, Brazil
| | - Thiago Mendonça de Aquino
- Laboratory of Medicinal Chemistry, Nursing and Pharmacy School, Federal University of Alagoas, Maceio-AL, Brazil
| | | | - João Xavier de Araújo-Júnior
- Laboratory of Medicinal Chemistry, Nursing and Pharmacy School, Federal University of Alagoas, Maceio-AL, Brazil
| | - Marina de M Silva
- Laboratory of Development and Instrumentation in Analytical Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio-AL, Brazil
| | - Maria Dayanne de A Dantas
- Laboratory of Development and Instrumentation in Analytical Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio-AL, Brazil
| | - Josué Carinhanha C Santos
- Laboratory of Development and Instrumentation in Analytical Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio-AL, Brazil
| | - Isis M Figueiredo
- Laboratory of Development and Instrumentation in Analytical Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio-AL, Brazil
| | - Marc-Antoine Bazin
- Universite de Nantes, Cibles et medicaments des infections et du cancer, IICiMed, EA1155, F-44000 Nantes, France
| | - Pascal Marchand
- Universite de Nantes, Cibles et medicaments des infections et du cancer, IICiMed, EA1155, F-44000 Nantes, France
| | - Teresinha Gonçalves da Silva
- Bioactive Products Prospecting Laboratory, Department of Antibiotics, Federal University of Pernambuco, Recife-PE, Brazil
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Jan R, Chaudhry GES. Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics. Adv Pharm Bull 2019; 9:205-218. [PMID: 31380246 PMCID: PMC6664112 DOI: 10.15171/apb.2019.024] [Citation(s) in RCA: 521] [Impact Index Per Article: 86.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 12/16/2018] [Accepted: 12/20/2018] [Indexed: 12/20/2022] Open
Abstract
Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.
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Affiliation(s)
- Rehmat Jan
- Institute of Marine Biotechnology, Universiti Terengganu Malaysia, 21030 Terengganu, Malaysia
| | - Gul-E-Saba Chaudhry
- Institute of Marine Biotechnology, Universiti Terengganu Malaysia, 21030 Terengganu, Malaysia
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Anticancer activity of grassy Hystrix brachyura bezoar and its mechanisms of action: An in vitro and in vivo based study. Biomed Pharmacother 2019; 114:108841. [PMID: 30981106 DOI: 10.1016/j.biopha.2019.108841] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/26/2019] [Accepted: 03/31/2019] [Indexed: 01/17/2023] Open
Abstract
Porcupine bezoar (PB) is a calcified undigested material generally found in porcupine's (Hystrix brachyura) gastrointestinal tract. The bezoar is traditionally used in South East Asia and Europe for the treatment of cancer, poisoning, dengue, typhoid, etc. However, limited scientific studies have been performed to verify its anticancer potential to substantiate its traditional claims in the treatment of cancers. Hence, this study was aimed at investigating the in vitro and in vivo anticancer properties of two grassy PB aqueous extract (PB-A and PB-B) using A375 cancer cell line and zebrafish model, respectively. This paper presents the first report on in vitro A375 cell viability assay, apoptosis assay, cell cycle arrest assay, migration assay, invasion assay, qPCR experimental assay and in vivo anti-angiogenesis assay using the grassy PBs. Experimental findings revealed IC50 value are 26.59 ± 1.37 μg/mL and 30.12 ± 3.25 μg/mL for PB-A and PB-B respectively. PBs showed anti-proliferative activity with no significant cytotoxic effect on normal human dermal fibroblast (NHDF). PBs were also found to induce apoptosis via intrinsic pathway and arrest cell cycle at G2/M phase. Additionally, the findings indicated its ability to debilitate migration and invasion of A375 cells. Further evaluation using embryo zebrafish model revealed LC50 = 450.0 ± 2.50 μg/mL and 58.7 ± 5.0 μg/mL for PB-A and PB-B which also exerted anti-angiogenesis effect in zebrafish. Moreover, stearic acid, ursodeoxycholic acid and pregnenolone were identified as possible metabolites that might contribute to the anticancer effect of the both PBs. Overall, this study demonstrated that PB-A and PB-B possess potential in vitro and in vivo anticancer effects which are elicited through selective cytotoxic effect, induction of apoptosis, inhibition of migration and invasion and anti-angiogenesis. This study provides scientific evidence that the porcupine bezoar do possess anti-cancer efficacy and further justifies its traditional utility. However, more experiments with higher vertebrae models are still warranted to validate its traditional claims as an anticancer agent.
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Dong Y, Qiu P, Zhu R, Zhao L, Zhang P, Wang Y, Li C, Chai K, Shou D, Zhao H. A Combined Phytochemistry and Network Pharmacology Approach to Reveal the Potential Antitumor Effective Substances and Mechanism of Phellinus igniarius. Front Pharmacol 2019; 10:266. [PMID: 30941044 PMCID: PMC6434905 DOI: 10.3389/fphar.2019.00266] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 03/04/2019] [Indexed: 12/13/2022] Open
Abstract
Phellinus igniarius (P. igniarius) is a medicinal fungus that is widely used in East Asia for the adjuvant treatment of cancer. To elucidate the antitumor effective substances and mechanism of P. igniarius, we designed an approach incorporating cytotoxicity screening, phytochemical analysis, network pharmacology construction, and cellular and molecular experiments. The dichloromethane extract of P. igniarius (DCMPI) was identified as the active portion in HT-29 cells. Nineteen constituents were identified, and 5 were quantified by UPLC-ESI-Q/TOF-MS. Eight ingredients were obtained in the network pharmacology study. In total, 473 putative targets associated with DCMPI and 350 putative targets related to colon cancer were derived from online databases and target prediction tools. Protein-protein interaction networks of drug and disease putative targets were constructed, and 84 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to reactive oxygen species (ROS) metabolic processes and intrinsic apoptotic pathways. Then, a cellular experiment was used to validate the drug-target mechanisms predicted by the system pharmacology analysis. Experimental results showed that DCMPI increased intracellular ROS levels and induced HT-29 cell apoptosis. Molecular biology experiments indicated that DCMPI not only increased Bax and Bad protein expression and promoted PARP and caspase-3/9 cleavage but also down-regulated Bcl-2 and Bcl-xl protein levels to induce apoptosis in HT-29 cells. In conclusion, our study provides knowledge on the chemical composition and antitumor mechanism of P. igniarius, which may be exploited as a promising therapeutic option for colon cancer.
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Affiliation(s)
- Yu Dong
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China.,College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ping Qiu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rui Zhu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lisha Zhao
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Pinghu Zhang
- Institute of Translational Medicine and Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College, Yangzhou University, Yangzhou, China
| | - Yiqi Wang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Changyu Li
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kequn Chai
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China.,College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.,Zhejiang Key Laboratory of Tumor Diagnosis and Treatment with Integrated TCM and Western Medicine, Hangzhou, China
| | - Dan Shou
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, China
| | - Huajun Zhao
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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Jiang W, Meng L, Xu G, Lv C, Wang H, Tian H, Chen R, Jiao B, Wang B, Huang C. Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF-1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase-3 signaling pathway in small cell lung cancer. Oncol Lett 2018; 16:6445-6457. [PMID: 30405782 PMCID: PMC6202482 DOI: 10.3892/ol.2018.9486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 03/26/2018] [Indexed: 12/13/2022] Open
Abstract
Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI-H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA in vitro and in vivo. Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells in vitro and in vivo by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future.
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Affiliation(s)
- Wenli Jiang
- Department of Biochemistry and Molecular Biology, The Faculty of Basic Medical Science, Second Military Medical University, Shanghai 200433, P.R. China
| | - Linghong Meng
- Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Experimental Marine Biology, Institute of Oceanology of The Chinese Academy of Sciences, Qingdao, Shandong 266071, P.R. China
| | - Guangming Xu
- Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Experimental Marine Biology, Institute of Oceanology of The Chinese Academy of Sciences, Qingdao, Shandong 266071, P.R. China
| | - Cuiting Lv
- Department of Biochemistry and Molecular Biology, The Faculty of Basic Medical Science, Second Military Medical University, Shanghai 200433, P.R. China
| | - Hongliang Wang
- College of Pharmacy, Shanghai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - He Tian
- Department of Pediatrics, Shanghai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Ruohua Chen
- Department of VIP Clinical, Shanghai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Binghua Jiao
- Department of Biochemistry and Molecular Biology, The Faculty of Basic Medical Science, Second Military Medical University, Shanghai 200433, P.R. China
| | - Bingui Wang
- Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Experimental Marine Biology, Institute of Oceanology of The Chinese Academy of Sciences, Qingdao, Shandong 266071, P.R. China
| | - Caiguo Huang
- Department of Biochemistry and Molecular Biology, The Faculty of Basic Medical Science, Second Military Medical University, Shanghai 200433, P.R. China
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Kong P, Chen L, Shi X, Pan H, Yu M, Ge H, Zhu J, Ma G, Li L, Ding Q, Zhou W, Wang S. Microwave ablation combined with doxorubicin enhances cell death via promoting reactive oxygen species generation in breast cancer cells. Diagn Interv Imaging 2018; 99:783-791. [PMID: 30037745 DOI: 10.1016/j.diii.2018.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 04/19/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE To evaluate the mechanism for enhancing cell death induced by microwave ablation (MWA) combined with doxorubicin treatment in breast cancer cells. MATERIALS AND METHODS Different temperatures of heat treatment were used to mimic the tumor affected by sublethal heat during MWA in vitro. Breast cancer cells were treated at 43°C and 45°C, with or without doxorubicin. Cell viability, apoptosis, and intracellular reactive oxygen species (ROS) were evaluated in MDA-MB-231 and SUM-1315 cells. Nude mice breast cancer models were randomly divided into control, MWA, doxorubicin, and combined treatment groups. Tumor apoptosis and DNA damage were evaluated in these groups. RESULTS The combined group had lower cell viability than the heat or doxorubicin group (all P<0.05), and enhanced apoptosis rate was observed in the combined group compared to others (all P<0.01) in MDA-MB-231 and SUM-1315. Increased capase3 (all P<0.01) and decreased Bcl-Xl (all P<0.01) were detected after combined therapy compared to single treated group in vitro. The raisedCaspase3 and DNA damage marker histone H2A.X induced by combined treatment were also approved in the nude mice models. Combined treatment promoted ROS generation compared to doxorubicin or MWA treatment (all P < 0.01). NF-κB expression in the combined group was higher than that of the single treatment group (all P<0.05). N-acetylcysteine (NAC), a ROS scavenger, partly restrained the combined treatment induced cell proliferation inhibition, Caspase3 and NF-κB compared to doxorubicin treatment (all P<0.05). CONCLUSION MWA combined with doxorubicin promote cell death via ROS induced cell apoptosis and DNA damage. Increasing ROS has potential for improving the efficiency of combined treatment.
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Affiliation(s)
- P Kong
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - L Chen
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - X Shi
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - H Pan
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - M Yu
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - H Ge
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - J Zhu
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - G Ma
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - L Li
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - Q Ding
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China
| | - W Zhou
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China.
| | - S Wang
- Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China.
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Arumugam A, Abdull Razis AF. Apoptosis as a Mechanism of the Cancer Chemopreventive Activity of Glucosinolates: a Review. Asian Pac J Cancer Prev 2018; 19:1439-1448. [PMID: 29936713 PMCID: PMC6103590 DOI: 10.22034/apjcp.2018.19.6.1439] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 05/29/2018] [Indexed: 01/27/2023] Open
Abstract
Cruciferous vegetables are a rich source of glucosinolates that have established anti-carcinogenic activity. Naturally-occurring glucosinolates and their derivative isothiocyanates (ITCs), generated as a result of their enzymatic degradation catalysed by myrosinase, have been linked to low cancer incidence in epidemiological studies, and in animal models isothiocyanates suppressed chemically-induced tumorigenesis. The prospective effect of isothiocyanates as anti-carcinogenic agent has been much explored as cytotoxic against wide array of cancer cell lines and being explored for the development of new anticancer drugs. However, the mechanisms of isothiocyanates in inducing apoptosis against tumor cell lines are still largely disregarded. A number of mechanisms are believed to be involved in the glucosinolate-induced suppression of carcinogenesis, including the induction of apoptosis, biotransformation of xenobiotic metabolism, oxidative stress, alteration of caspase activity, angiogenesis, histone deacytylation and cell cycle arrest. The molecular mechanisms through which isothiocyanates stimulate apoptosis in cancer cell lines have not so far been clearly defined. This review summarizes the underlying mechanisms through which isothiocyanates modify the apoptotic pathway leading to cell death.
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Affiliation(s)
- Asvinidevi Arumugam
- Laboratory of UPM-MAKNA Cancer Research, Institute of Bioscience, University Putra Malaysia, 43400, UPM Serdang, Selangor, Malaysia.
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