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Rojas A, González I, Morales MA. Natural products and cancer: The urgent need to bridge the gap between preclinical and clinical research. World J Gastrointest Oncol 2025; 17:100484. [DOI: 10.4251/wjgo.v17.i4.100484] [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: 08/17/2024] [Revised: 01/20/2025] [Accepted: 01/27/2025] [Indexed: 03/25/2025] Open
Abstract
Any new report on the anticancer properties of natural products always awakens new satisfaction and hope about the role of the international scientific community in its continuous contributions to human health, particularly when those reports contribute to both the understanding and therapeutics of cancer. For many decades, natural products have been pivotal in drug discovery programs because they offer a diverse array of anticancer therapeutic possibilities. Recently, two manuscripts published in the World Journal of Gastrointestinal Oncology added new data to the already extensive body of anticancer preclinical evidence for resveratrol and senegenin, two compounds widely present in herbal preparations used in traditional Chinese medicine. The first one, with comprehensive and recognized anticancer properties, and the second one, shows a compelling body of evidence supporting its neuroprotective effects, but with emerging anticancer activities. Natural products have become key elements in the expanding and dynamic field of anticancer drug discovery. However, urgent and collective efforts are still needed to bridge the gap between preclinical and clinical research and thus bring new anticancer therapeutic breakthroughs.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana González
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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2
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Ghazizadeh M, Khorsandi K, Najafi SMA. Synergic anti-tumor effects of photodynamic therapy and resveratrol on triple-negative breast cancer cells. Photochem Photobiol Sci 2025:10.1007/s43630-025-00698-8. [PMID: 40095354 DOI: 10.1007/s43630-025-00698-8] [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: 06/04/2024] [Accepted: 02/24/2025] [Indexed: 03/19/2025]
Abstract
INTRODUCTION Breast cancer is a widespread type of cancer found across the world. The use of chemotherapy in breast cancer treatment may result in side effects and the emergence of drug resistance. Hence, seeking new and efficient therapies that reduce adverse reactions is imperative. Recently, combination therapy has emerged as a fresh and innovative strategy in contrast to conventional treatment methods. Photodynamic therapy (PDT) serves as a highly effective and minimally invasive technique for addressing breast cancer, providing the option to be utilized either concurrently or in conjunction with other therapeutic approaches. Resveratrol (RES) is a polyphenol found in several food sources. Research has demonstrated that RES can inhibit cell proliferation and metastasis and trigger apoptosis in tumor cells. This research aimed to assess the impact of combining RES and photodynamic therapy on MDA-MB-231 breast cancer cells. METHODS MDA-MB-231 cells were grown in culture and subsequently exposed to different methylene blue (MB) doses while subjected to laser irradiation (PDT). Following this treatment, the cells were exposed to different RES concentrations. Cell viability was assessed utilizing the MTT assay. Light and fluorescence microscopy (AO/EB staining) were employed to observe cell morphological alterations following exposure to RES and MB-PDT. Additionally, flow cytometry was utilized to investigate cell cycle progression and apoptosis induction. RESULTS The findings indicated that the co-administration of MB-PDT and RES resulted in increased cytotoxic effects on MDA-MB-231 breast cancer cells compared to the individual application of either treatment. DISCUSSION The results of this study suggest that MB-PDT can reduce the dose and time of RES treatment and, therefore, can be indicated as a new approach for treating breast cancer cells.
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Affiliation(s)
- Masta Ghazizadeh
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
| | - Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran.
| | - SMahmoud A Najafi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
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Das A, Mitra A, Ghosh S, Sarkar S, Pal PK, Bandyopadhyay D, Chattopadhyay S. Arsenic-induced transition of thymic inflammation-to-fibrosis involves Stat3-Twist1 interaction: Melatonin to the rescue. Biofactors 2025; 51:e2110. [PMID: 39096306 DOI: 10.1002/biof.2110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 07/19/2024] [Indexed: 08/05/2024]
Abstract
Groundwater arsenic is a notorious toxicant and exposure to environmentally relevant concentrations persists as a healthcare burden across the world. Arsenic has been reported to jeopardize the normal functioning of the immune system, but there are still gaps in the understanding of thymic T cell biology. Immunotoxic influence of arsenic in thymic integrity demands a potent restorative molecule. The objectives of this study were to examine key signaling cross-talks associated with arsenic-induced immune alterations in the thymus and propose melatonin as a potential candidate against immunological complications arising from arsenic exposure. Swiss albino mice were exposed to sodium arsenite (0.05 mg/L; in drinking water) and melatonin (IP:10 mg/kg BW) for 28 days. Melatonin successfully protected thymus from arsenic-mediated tissue degeneration and maintained immune homeostasis including T cell maturation and proliferation by mitigating oxidative stress through Nrf2 upregulation. Additionally, melatonin exerted ameliorative effect against arsenic-induced apoptosis and inflammation by inhibiting p53-mediated mitochondrial cell death pathway and NF-κB-p65/STAT3-mediated proinflammatory pathway, respectively. For the first time, we showed that arsenic-induced profibrotic changes were inhibited by melatonin through targeting of inflammation-associated EMT. Our findings clearly demonstrate that melatonin can be a viable and promising candidate in combating arsenic-induced immune toxicity with no collateral damage, making it an important research target.
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Affiliation(s)
- Ankur Das
- Department of Physiology, University of Calcutta, Kolkata, India
| | - Ankan Mitra
- Department of Physiology, University of Calcutta, Kolkata, India
| | - Sourav Ghosh
- Department of Physiology, University of Calcutta, Kolkata, India
| | - Swaimanti Sarkar
- Department of Physiology, University of Calcutta, Kolkata, India
| | - Palash Kumar Pal
- Department of Physiology, University of Calcutta, Kolkata, India
| | | | - Sreya Chattopadhyay
- Department of Physiology, University of Calcutta, Kolkata, India
- Centre for Research in Nanoscience and Nanotechnology (CRNN), University of Calcutta, Kolkata, India
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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Kaveh Zenjanab M, Hashemzadeh N, Alimohammadvand S, Sharifi-Azad M, Dalir Abdolahinia E, Jahanban-Esfahlan R. Notch Signaling Suppression by Golden Phytochemicals: Potential for Cancer Therapy. Adv Pharm Bull 2024; 14:302-313. [PMID: 39206407 PMCID: PMC11347744 DOI: 10.34172/apb.2024.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/09/2024] [Accepted: 03/03/2024] [Indexed: 09/04/2024] Open
Abstract
Cancer is one of the main causes of mortality worldwide. Cancer cells are characterized by unregulated cellular processes, including proliferation, progression, and angiogenesis. The occurrence of these processes is due to the dysregulation of various signaling pathways such as NF-κB (nuclear factor-κB), Wnt/beta-catenin, Notch signaling and MAPK (mitogen-activated protein kinases). Notch signaling pathways cause the progression of various types of malignant tumors. Among the phytochemicals for cancer therapy, several have attracted great interest, including curcumin, genistein, quercetin, silibinin, resveratrol, cucurbitacin and glycyrrhizin. Given the great cellular and molecular heterogeneity within tumors and the high toxicity and side effects of synthetic chemotherapeutics, natural products with pleiotropic effects that simultaneously target numerous signaling pathways appear to be ideal substitutes for cancer therapy. With this in mind, we take a look at the current status, impact and potential of known compounds as golden phytochemicals on key signaling pathways in tumors, focusing on the Notch pathway. This review may be useful for discovering new molecular targets for safe and efficient cancer therapy with natural chemotherapeutics.
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Affiliation(s)
| | - Nastaran Hashemzadeh
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Alimohammadvand
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Masoumeh Sharifi-Azad
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elaheh Dalir Abdolahinia
- Department of Oral Science and Translation Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, US
| | - Rana Jahanban-Esfahlan
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Shaban NZ, Hegazy WA, Abu-Serie MM, Talaat IM, Awad OM, Habashy NH. Seedless black Vitis vinifera polyphenols suppress hepatocellular carcinoma in vitro and in vivo by targeting apoptosis, cancer stem cells, and proliferation. Biomed Pharmacother 2024; 175:116638. [PMID: 38688169 DOI: 10.1016/j.biopha.2024.116638] [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: 01/27/2024] [Revised: 04/04/2024] [Accepted: 04/22/2024] [Indexed: 05/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor and one of the most challenging cancers to treat. Here, we evaluated the in vitro and in vivo ameliorating impacts of seedless black Vitis vinifera (VV) polyphenols on HCC. Following the preparation of the VV crude extract (VVCE) from seedless VV (pulp and skin), three fractions (VVF1, VVF2, and VVF3) were prepared. The anticancer potencies of the prepared fractions, compared to 5-FU, were assessed against HepG2 and Huh7 cells. In addition, the effects of these fractions on p-dimethylaminoazobenzene-induced HCC in mice were evaluated. The predicted impacts of selected phenolic constituents of VV fractions on the activity of essential HCC-associated enzymes (NADPH oxidase "NADPH-NOX2", histone deacetylase 1 "HDAC1", and sepiapterin reductase "SepR") were analyzed using molecular docking. The results showed that VVCE and its fractions induced apoptosis and collapsed CD133+ stem cells in the studied cancer cell lines with an efficiency greater than 5-FU. VVF1 and VVF2 exhibited the most effective anticancer fractions in vitro; therefore, we evaluated their influences in mice. VVF1 and VVF2 improved liver morphology and function, induced apoptosis, and lowered the fold expression of various crucial genes that regulate cancer stem cells and other vital pathways for HCC progression. For most of the examined parameters, VVF1 and VVF2 had higher potency than 5-FU, and VVF1 showed more efficiency than VVF2. The selected phenolic compounds displayed competitive inhibitory action on NADPH-NOX2, HDAC1, and SepR. In conclusion, these findings declare that VV polyphenolic fractions, particularly VVF1, could be promising safe anti-HCC agents.
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Affiliation(s)
- Nadia Z Shaban
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt.
| | - Walaa A Hegazy
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt.
| | - Marwa M Abu-Serie
- Department of Medical Biotechnology, Genetic Engineering, and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg EL-Arab, Alexandria 21934, Egypt
| | - Iman M Talaat
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; Clinical Sciences Department, College of Medicine, University of Sharjah, United Arab Emirates.
| | - Olfat M Awad
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt.
| | - Noha H Habashy
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt
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Bhuia MS, Chowdhury R, Akter MA, Ali MA, Afroz M, Akbor MS, Sonia FA, Mubarak MS, Islam MT. A mechanistic insight into the anticancer potentials of resveratrol: Current perspectives. Phytother Res 2024. [PMID: 38768953 DOI: 10.1002/ptr.8239] [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: 11/11/2023] [Revised: 04/17/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024]
Abstract
Resveratrol is a widely recognized polyphenolic phytochemical found in various plants and their fruits, such as peanuts, grapes, and berry fruits. It is renowned for its several health advantages. The phytochemical is well known for its anticancer properties, and a substantial amount of clinical evidence has also established its promise as a chemotherapeutic agent. This study focuses on assessing the anticancer properties of resveratrol and gaining insight into the underlying molecular mechanisms. It also evaluates the biopharmaceutical, toxicological characteristics, and clinical utilization of resveratrol to determine its suitability for further development as a reliable anticancer agent. Therefore, the information about preclinical and clinical studies was collected from different electronic databases up-to-date (2018-2023). Findings from this study revealed that resveratrol has potent therapeutic benefits against various cancers involving different molecular mechanisms, such as induction of oxidative stress, cytotoxicity, inhibition of cell migration and invasion, autophagy, arresting of the S phase of the cell cycle, apoptotic, anti-angiogenic, and antiproliferative effects by regulating different molecular pathways including PI3K/AKT, p38/MAPK/ERK, NGFR-AMPK-mTOR, and so on. However, the compound has poor oral bioavailability due to reduced absorption; this limitation is overcome by applying nanotechnology (nanoformulation of resveratrol). Clinical application also showed therapeutic benefits in several types of cancer with no serious adverse effects. We suggest additional extensive studies to further check the efficacy, safety, and long-term hazards. This could involve a larger number of clinical samples to establish the compound as a reliable drug in the treatment of cancer.
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Affiliation(s)
- Md Shimul Bhuia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Dhaka, Bangladesh
| | - Raihan Chowdhury
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Dhaka, Bangladesh
| | - Mst Asma Akter
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Md Arman Ali
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Meher Afroz
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Md Showkot Akbor
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Fatema Akter Sonia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | | | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Dhaka, Bangladesh
- Pharmacy Discipline, Khulna University, Khulna, Bangladesh
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Viegas S, Marinheiro D, Bastos V, Daniel-da-Silva AL, Vieira R, Oliveira H, Almeida JC, Ferreira BJML. Resveratrol-Loaded Polydimethylsiloxane-Silica Hybrid Materials: Synthesis, Characterization, and Antitumoral Activity. Polymers (Basel) 2024; 16:879. [PMID: 38611137 PMCID: PMC11013690 DOI: 10.3390/polym16070879] [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: 02/05/2024] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024] Open
Abstract
In this work, hybrid materials within the polydimethylsiloxane-silica (PDMS-SiO2) system, synthesized via the sol-gel method, were developed and characterized for their potential to incorporate and release the bioactive compound resveratrol (RES). RES was incorporated into the materials with a high loading efficiency (>75%) using the rotary evaporator technique. This incorporation induced the amorphization of RES, resulting in enhanced solubility and in vitro release when compared to the free polyphenolic compound. The release profiles displayed pH dependence, exhibiting notably faster release at pH 5.2 compared to pH 7.4. The gradual release of RES over time demonstrated an initial time lag of approximately 4 h, being well described by the Weibull model. In vitro cytotoxicity studies were conducted on human osteosarcoma cells (MG-63), revealing a concentration-dependent decrease in cell viability for RES-loaded samples (for concentrations >50 µg mL-1).
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Affiliation(s)
- Sofia Viegas
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Diogo Marinheiro
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Verónica Bastos
- Department of Biology, CESAM-Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal (H.O.)
| | - Ana L. Daniel-da-Silva
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ricardo Vieira
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Helena Oliveira
- Department of Biology, CESAM-Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal (H.O.)
| | - José Carlos Almeida
- Department of Materials and Ceramic Engineering, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara J. M. L. Ferreira
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
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Brockmueller A, Sajeev A, Koklesova L, Samuel SM, Kubatka P, Büsselberg D, Kunnumakkara AB, Shakibaei M. Resveratrol as sensitizer in colorectal cancer plasticity. Cancer Metastasis Rev 2024; 43:55-85. [PMID: 37507626 PMCID: PMC11016130 DOI: 10.1007/s10555-023-10126-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Lenka Koklesova
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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Liu Y, Jiang B, Li Y, Zhang X, Wang L, Yao Y, Zhu B, Shi H, Chai X, Hu X, Zhang B, Li H. Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets. Medicine (Baltimore) 2024; 103:e36467. [PMID: 38241548 PMCID: PMC10798715 DOI: 10.1097/md.0000000000036467] [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: 05/30/2023] [Accepted: 11/14/2023] [Indexed: 01/21/2024] Open
Abstract
Osteosarcoma (OS) has a high recurrence rate, disability rate, mortality and metastasis, it brings great economic burden and psychological pressure to patients, and then seriously affects the quality of life of patients. At present, the treatment methods of OS mainly include radiotherapy, chemotherapy, surgical therapy and neoadjuvant chemotherapy combined with limb salvage surgery. These treatment methods can relieve the clinical symptoms of patients to a certain extent, and also effectively reduce the disability rate, mortality and recurrence rate of OS patients. However, because metastasis of tumor cells leads to new complications, and OS cells become resistant with prolonged drug intervention, which reduces the sensitivity of OS cells to drugs, these treatments still have some limitations. More and more studies have shown that traditional Chinese medicine (TCM) has the characteristics of "multiple targets and multiple pathways," and can play an important role in the development of OS through several key signaling pathways, including PI3K/AKT, Wnt/β-catenin, tyrosine kinase/transcription factor 3 (JAK/STAT3), Notch, transforming growth factor-β (TGF-β)/Smad, nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nuclear factor E2-related factor 2 (Nrf2), Hippo/YAP, OPG/RANK/RANKL, Hedgehog and so on. In this paper, the signaling pathways of cross-interference between active ingredients of TCM and OS were reviewed, and the development status of novel OS treatment was analyzed. The active ingredients in TCM can provide therapeutic benefits to patients by targeting the activity of signaling pathways. In addition, potential strategies for targeted therapy of OS by using ferroptosis were discussed. We hope to provide a unique insight for the in-depth research and clinical application of TCM in the fields of OS growth, metastasis and chemotherapy resistance by understanding the signaling crosstalk between active ingredients in TCM and OS.
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Affiliation(s)
- Yuezhen Liu
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Bing Jiang
- Department of Integrated Chinese and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yanqiang Li
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xiaoshou Zhang
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Lijun Wang
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yasai Yao
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Baohong Zhu
- Clinical College of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Hengwei Shi
- The Second Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xiping Chai
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Xingrong Hu
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Bangneng Zhang
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Hongzhuan Li
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
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Zarezadeh SM, Sharafi AM, Erabi G, Tabashiri A, Teymouri N, Mehrabi H, Golzan SA, Faridzadeh A, Abdollahifar Z, Sami N, Arabpour J, Rahimi Z, Ansari A, Abbasi MR, Azizi N, Tamimi A, Poudineh M, Deravi N. Natural STAT3 Inhibitors for Cancer Treatment: A Comprehensive Literature Review. Recent Pat Anticancer Drug Discov 2024; 19:403-502. [PMID: 37534488 DOI: 10.2174/1574892818666230803100554] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 06/05/2023] [Accepted: 06/09/2023] [Indexed: 08/04/2023]
Abstract
Cancer is one of the leading causes of mortality and morbidity worldwide, affecting millions of people physically and financially every year. Over time, many anticancer treatments have been proposed and studied, including synthetic compound consumption, surgical procedures, or grueling chemotherapy. Although these treatments have improved the daily life quality of patients and increased their survival rate and life expectancy, they have also shown significant drawbacks, including staggering costs, multiple side effects, and difficulty in compliance and adherence to treatment. Therefore, natural compounds have been considered a possible key to overcoming these problems in recent years, and thorough research has been done to assess their effectiveness. In these studies, scientists have discovered a meaningful interaction between several natural materials and signal transducer and activator of transcription 3 molecules. STAT3 is a transcriptional protein that is vital for cell growth and survival. Mechanistic studies have established that activated STAT3 can increase cancer cell proliferation and invasion while reducing anticancer immunity. Thus, inhibiting STAT3 signaling by natural compounds has become one of the favorite research topics and an attractive target for developing novel cancer treatments. In the present article, we intend to comprehensively review the latest knowledge about the effects of various organic compounds on inhibiting the STAT3 signaling pathway to cure different cancer diseases.
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Affiliation(s)
- Seyed Mahdi Zarezadeh
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Mohammad Sharafi
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gisou Erabi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Arefeh Tabashiri
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navid Teymouri
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hoda Mehrabi
- Student Research Committee, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Seyyed Amirhossein Golzan
- Student Research Committee, Department of Food Science and Technology, National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Abdollahifar
- Student Research Committee, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Nafiseh Sami
- Student Research Committee, Tehran Medical Sciences, Islamic Azad University Medical Branch of Tehran, Tehran, Iran
| | - Javad Arabpour
- Department of Microbiology, Faculty of New Sciences, Islamic Azad University Medical Branch of Tehran, Tehran, Iran
| | - Zahra Rahimi
- School of Medicine, Zanjan University of Medical Sciences Zanjan, Iran
| | - Arina Ansari
- Student Research Committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | | | - Nima Azizi
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Kursvietiene L, Kopustinskiene DM, Staneviciene I, Mongirdiene A, Kubová K, Masteikova R, Bernatoniene J. Anti-Cancer Properties of Resveratrol: A Focus on Its Impact on Mitochondrial Functions. Antioxidants (Basel) 2023; 12:2056. [PMID: 38136176 PMCID: PMC10740678 DOI: 10.3390/antiox12122056] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Cancer is one of the most serious public health issues worldwide, demanding ongoing efforts to find novel therapeutic agents and approaches. Amid growing interest in the oncological applications of phytochemicals, particularly polyphenols, resveratrol-a naturally occurring polyphenolic stilbene derivative-has emerged as a candidate of interest. This review analyzes the pleiotropic anti-cancer effects of resveratrol, including its modulation of apoptotic pathways, cell cycle regulation, inflammation, angiogenesis, and metastasis, its interaction with cancer stem cells and the tumor microenvironment. The effects of resveratrol on mitochondrial functions, which are crucial to cancer development, are also discussed. Future research directions are identified, including the elucidation of specific molecular targets, to facilitate the clinical translation of resveratrol in cancer prevention and therapy.
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Affiliation(s)
- Lolita Kursvietiene
- Department of Biochemistry, Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009 Kaunas, Lithuania (I.S.); (A.M.)
| | - Dalia M. Kopustinskiene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
| | - Inga Staneviciene
- Department of Biochemistry, Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009 Kaunas, Lithuania (I.S.); (A.M.)
| | - Ausra Mongirdiene
- Department of Biochemistry, Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, Eiveniu str. 4, LT-50009 Kaunas, Lithuania (I.S.); (A.M.)
| | - Kateřina Kubová
- Department of Pharmaceutical Technology, Masaryk University, 60177 Brno, Czech Republic; (K.K.); (R.M.)
| | - Ruta Masteikova
- Department of Pharmaceutical Technology, Masaryk University, 60177 Brno, Czech Republic; (K.K.); (R.M.)
| | - Jurga Bernatoniene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania
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13
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Bi M, Qin Y, Wang L, Zhang J. The protective role of resveratrol in diabetic wound healing. Phytother Res 2023; 37:5193-5204. [PMID: 37767805 DOI: 10.1002/ptr.7981] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/23/2023] [Accepted: 07/28/2023] [Indexed: 09/29/2023]
Abstract
Diabetic wounds are severe complications of diabetes mellitus (DM), which have difficulty in healing. Although diverse treatments have been used, the prognosis of diabetic wounds is not satisfactory; therefore, an effective therapy to accelerate diabetic wound healing is urgently needed. In our review, we summarized that resveratrol can promote diabetic wound healing by protecting against hyperglycemia, inflammation, oxidative stress, vascular pathology, infection, and peripheral neuropathy. To clarify it clearly, we highlighted its underlying mechanisms of protective effects of resveratrol against diabetic wounds, and high-quality studies are needed to firmly establish its clinical efficacy. Otherwise, with the development of material sciences, resveratrol can exert its therapeutic effectiveness efficiently; however, more high-quality studies are needed to confirm the clinical efficacy of resveratrol on diabetic wounds.
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Affiliation(s)
- Minglei Bi
- Department of Plastic Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yonghong Qin
- Department of Plastic Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Lerong Wang
- Department of Plastic Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Jin Zhang
- Department of Plastic Surgery, Lanzhou University Second Hospital, Lanzhou, China
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14
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Cimmino A, Fasciglione GF, Gioia M, Marini S, Ciaccio C. Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma. Int J Mol Sci 2023; 24:13344. [PMID: 37686148 PMCID: PMC10487502 DOI: 10.3390/ijms241713344] [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: 08/02/2023] [Revised: 08/19/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.
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Affiliation(s)
| | | | | | | | - Chiara Ciaccio
- Department of Clinical Sciences and Translational Medicine, University of Rome ‘Tor Vergata’, Via Montpellier 1, I-00133 Rome, Italy; (A.C.); (G.F.F.); (M.G.); (S.M.)
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15
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Zhu WT, Zeng XF, Yang H, Jia ML, Zhang W, Liu W, Liu SY. Resveratrol Loaded by Folate-Modified Liposomes Inhibits Osteosarcoma Growth and Lung Metastasis via Regulating JAK2/STAT3 Pathway. Int J Nanomedicine 2023; 18:2677-2691. [PMID: 37228445 PMCID: PMC10204760 DOI: 10.2147/ijn.s398046] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/14/2023] [Indexed: 05/27/2023] Open
Abstract
Background Osteosarcoma is a malignant bone tumor with a high rate of lung metastasis and mortality. It has been demonstrated that resveratrol can inhibit tumor proliferation and metastasis, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare folate-modified liposomes loaded with resveratrol to investigate its anti-osteosarcoma effect in vitro and in vivo. Methods We prepared and characterized resveratrol liposomes modified with folate (denoted as, FA-Res/Lps). The effects of FA-Res/Lps on human osteosarcoma cell 143B proliferation, apoptosis, and migration were investigated by MTT, cell cloning, wound-healing assay, transwell, and flow cytometry. A xenograft tumor and lung metastasis model of osteosarcoma was constructed to study the therapeutic effects of FA-Res/Lps on the growth and metastasis of osteosarcoma in vivo. Results The FA-Res/Lps were prepared with a particle size of 118.5 ± 0.71 and a small dispersion coefficient of 0.154 ± 0.005. We found that FA-modified liposomes significantly increased resveratrol uptake by osteosarcoma cells 143B in flow cytometric assay, resulting in FA-Res/Lps, which inhibit tumor proliferation, migration and induce apoptosis more effectively than free Res and Res/Lps. The mechanism of action may be associated with the inhibition of JAK2/STAT3 signaling. In vivo imaging demonstrated that FA-modified DiR-modified liposomes significantly increased the distribution of drugs at the tumor site, leading to significant inhibition of osteosarcoma growth and metastasis by FA-Res/Lps. Furthermore, we found that FA-Res/Lps did not cause any adverse effects on mice body weight, liver, or kidney tissues. Conclusion Taken together, the anti-osteosarcoma effect of resveratrol is significantly enhanced when it is loaded into FA-modified liposomes. FA-Res/Lps is a promising strategy for the treatment of osteosarcoma.
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Affiliation(s)
- Wen Ting Zhu
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, People’s Republic of China
| | - Xiang Feng Zeng
- Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China
| | - Hua Yang
- Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China
| | - Meng Lei Jia
- Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, People’s Republic of China
| | - Wei Zhang
- Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China
| | - Wei Liu
- Department of Orthopedics, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China
| | - Sheng Yao Liu
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China
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16
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Passeri G, Vincent RA, Xiao Z, Northcote-Smith J, Suntharalingam K. Encapsulation and Delivery of an Osteosarcoma Stem Cell Active Gallium(III)-Diflunisal Complex Using Polymeric Micelles. ChemMedChem 2023; 18:e202200599. [PMID: 36533570 DOI: 10.1002/cmdc.202200599] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/22/2022] [Accepted: 12/17/2022] [Indexed: 12/23/2022]
Abstract
Here we report the encapsulation of an osteosarcoma stem cell (OSC) potent gallium(III)-diflunisal complex 1 into polymeric nanoparticles, and its delivery into osteosarcoma cells. At the optimum feed (20 %, 1 NP20 ), nanoparticle encapsulation of 1 enhances potency towards bulk osteosarcoma cells and OSCs (cultured in monolayer and three-dimensional systems). Strikingly, the nanoparticle formulation exhibits up to 5645-fold greater potency towards OSCs than frontline anti-osteosarcoma drugs, doxorubicin and cisplatin. The nanoparticle formulation evokes a similar mechanism of action as the payload, which bodes well for future translation. Specifically, the nanoparticle formulation induces nuclear DNA damage, cyclooxygenase-2 downregulation, and caspase-dependent apoptosis. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver an OSC-active metal complex into osteosarcoma cells.
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Affiliation(s)
- Ginevra Passeri
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK
| | - Ruby A Vincent
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK
| | - Zhiyin Xiao
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK.,College of Biological, Chemical Sciences and Engineering, Jiaxing University, 314001, Jiaxing, Zhejiang Province, P. R. China
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17
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Vincent RA, Passeri G, Northcote-Smith J, Singh K, Suntharalingam K. The Osteosarcoma Stem Cell Activity of a Gallium(III)-Phenanthroline Complex Appended to Salicylate. Chembiochem 2022; 23:e202200532. [PMID: 36281941 PMCID: PMC10099568 DOI: 10.1002/cbic.202200532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/24/2022] [Indexed: 01/25/2023]
Abstract
We report the synthesis, characterisation, and anti-osteosarcoma properties of a gallium(III) complex (1) comprising of two 1,10-phenanthroline ligands and salicylate, a non-steroidal anti-inflammatory drug. The gallium(III) complex 1 displays micromolar potency towards bulk osteosarcoma cells and osteosarcoma stem cells (OSCs). Notably, the gallium(III) complex 1 exhibits significantly higher toxicity towards OSCs grown in monolayer and three-dimensional cultures than cisplatin, a frontline anti-osteosarcoma drug. Nuclei isolation and immunoblotting studies show that the gallium(III) complex 1 enters osteosarcoma cell nuclei and induces DNA damage. Flow cytometry and cytotoxicity studies (in the presence of prostaglandin E2) indicate that the gallium(III) complex 1 downregulates cyclooxygenase-2 (COX-2) expression and kills osteosarcoma cells in a COX-2-dependent manner. Further, the mode of osteosarcoma cell death evoked by the gallium(III) complex 1 is characterised as caspase-dependent apoptosis.
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Affiliation(s)
- Ruby A Vincent
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK
| | - Ginevra Passeri
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK
| | | | - Kuldip Singh
- School of Chemistry, University of Leicester, LE1 7RH, Leicester, UK
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18
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Asma ST, Acaroz U, Imre K, Morar A, Shah SRA, Hussain SZ, Arslan-Acaroz D, Demirbas H, Hajrulai-Musliu Z, Istanbullugil FR, Soleimanzadeh A, Morozov D, Zhu K, Herman V, Ayad A, Athanassiou C, Ince S. Natural Products/Bioactive Compounds as a Source of Anticancer Drugs. Cancers (Basel) 2022; 14:6203. [PMID: 36551687 PMCID: PMC9777303 DOI: 10.3390/cancers14246203] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of other plant-derived bioactive compounds are in the clinical development phase against cancer, such as gimatecan, elomotecan, etc. Additionally, the conjugation of natural compounds with anti-cancerous drugs, or some polymeric carriers particularly targeted to epitopes on the site of interest to tumors, can generate effective targeted treatment therapies. Cognizance from such pharmaceutical research studies would yield alternative drug development strategies through natural sources which could be economical, more reliable, and safe to use.
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Affiliation(s)
- Syeda Tasmia Asma
- Department of Food Hygiene and Technology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Turkey
| | - Ulas Acaroz
- Department of Food Hygiene and Technology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Turkey
- ACR Bio Food and Biochemistry Research and Development, Afyonkarahisar 03200, Turkey
| | - Kálmán Imre
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences “King Mihai I” from Timișoara, 300645 Timisoara, Romania
| | - Adriana Morar
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences “King Mihai I” from Timișoara, 300645 Timisoara, Romania
| | - Syed Rizwan Ali Shah
- Department of Animal Nutrition and Nutritional Diseases, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Turkey
| | - Syed Zajif Hussain
- Department of Chemistry and Chemical Engineering, SBA School of Science & Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore 54792, Pakistan
| | - Damla Arslan-Acaroz
- ACR Bio Food and Biochemistry Research and Development, Afyonkarahisar 03200, Turkey
- Department of Biochemistry, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Turkey
| | - Hayri Demirbas
- Department of Neurology, Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar 03030, Turkey
| | - Zehra Hajrulai-Musliu
- Department of Chemistry, Faculty of Veterinary Medicine, Ss. Cyril and Methodius University of Skopje, 1000 Skopje, North Macedonia
| | - Fatih Ramazan Istanbullugil
- Department of Chemistry and Technology, Faculty of Veterinary Medicine, Kyrgyz-Turkish Manas University, Bishkek KG-720038, Kyrgyzstan
| | - Ali Soleimanzadeh
- Department of Theriogenology, Faculty of Veterinary Medicine, Urmia University, Urmia 5756151818, Iran
| | - Dmitry Morozov
- Department of Epizootology and Infectious Diseases, Vitebsk State Academy of Veterinary Medicine, 210026 Vitebsk, Belarus
| | - Kui Zhu
- National Center for Veterinary Drug Safety Evaluation, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Viorel Herman
- Department of Infectious Disease and Preventive Medicine, Faculty of Veterinary Medicine, University of Life Sciences “King Mihai I” from Timișoara, 300645 Timisoara, Romania
| | - Abdelhanine Ayad
- Department of Physical Biology and Chemistry, Faculty of Nature and Life Sciences, Université de Bejaia, Bejaia 06000, Algeria
| | - Christos Athanassiou
- Laboratory of Entomology and Agriculture Zoology, Department of Agriculture, Crop Production and Rural Environment, University of Thessaly, 38446 Volos, Greece
| | - Sinan Ince
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Turkey
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19
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Tarone L, Mareschi K, Tirtei E, Giacobino D, Camerino M, Buracco P, Morello E, Cavallo F, Riccardo F. Improving Osteosarcoma Treatment: Comparative Oncology in Action. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122099. [PMID: 36556464 PMCID: PMC9783386 DOI: 10.3390/life12122099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022]
Abstract
Osteosarcoma (OSA) is the most common pediatric malignant bone tumor. Although surgery together with neoadjuvant/adjuvant chemotherapy has improved survival for localized OSA, most patients develop recurrent/metastatic disease with a dismally poor outcome. Therapeutic options have not improved for these OSA patients in recent decades. As OSA is a rare and "orphan" tumor, with no distinct targetable driver antigens, the development of new efficient therapies is still an unmet and challenging clinical need. Appropriate animal models are therefore critical for advancement in the field. Despite the undoubted relevance of pre-clinical mouse models in cancer research, they present some intrinsic limitations that may be responsible for the low translational success of novel therapies from the pre-clinical setting to the clinic. From this context emerges the concept of comparative oncology, which has spurred the study of pet dogs as a uniquely valuable model of spontaneous OSA that develops in an immune-competent system with high biological and clinical similarities to corresponding human tumors, including in its metastatic behavior and resistance to conventional therapies. For these reasons, the translational power of studies conducted on OSA-bearing dogs has seen increasing recognition. The most recent and relevant veterinary investigations of novel combinatorial approaches, with a focus on immune-based strategies, that can most likely benefit both canine and human OSA patients have been summarized in this commentary.
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Affiliation(s)
- Lidia Tarone
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
| | - Katia Mareschi
- Department of Public Health and Paediatrics, University of Torino, Piazza Polonia 94, 10126 Torino, Italy
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Department, Regina Margherita Children’s Hospital, City of Health and Science of Torino, 10126 Torino, Italy
| | - Elisa Tirtei
- Department of Public Health and Paediatrics, University of Torino, Piazza Polonia 94, 10126 Torino, Italy
- Stem Cell Transplantation and Cellular Therapy Laboratory, Paediatric Onco-Haematology Department, Regina Margherita Children’s Hospital, City of Health and Science of Torino, 10126 Torino, Italy
| | - Davide Giacobino
- Department of Veterinary Sciences, University of Torino, Largo Paolo Braccini 2, Grugliasco, 10095 Torino, Italy
| | - Mariateresa Camerino
- Department of Veterinary Sciences, University of Torino, Largo Paolo Braccini 2, Grugliasco, 10095 Torino, Italy
| | - Paolo Buracco
- Department of Veterinary Sciences, University of Torino, Largo Paolo Braccini 2, Grugliasco, 10095 Torino, Italy
| | - Emanuela Morello
- Department of Veterinary Sciences, University of Torino, Largo Paolo Braccini 2, Grugliasco, 10095 Torino, Italy
| | - Federica Cavallo
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
- Correspondence: (F.C.); (F.R.)
| | - Federica Riccardo
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
- Correspondence: (F.C.); (F.R.)
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20
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Lo Iacono M, Gaggianesi M, Bianca P, Brancato OR, Muratore G, Modica C, Roozafzay N, Shams K, Colarossi L, Colarossi C, Memeo L, Turdo A, Veschi V, Di Franco S, Todaro M, Stassi G. Destroying the Shield of Cancer Stem Cells: Natural Compounds as Promising Players in Cancer Therapy. J Clin Med 2022; 11:6996. [PMID: 36498571 PMCID: PMC9737492 DOI: 10.3390/jcm11236996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
In a scenario where eco-sustainability and a reduction in chemotherapeutic drug waste are certainly a prerogative to safeguard the biosphere, the use of natural products (NPs) represents an alternative therapeutic approach to counteract cancer diseases. The presence of a heterogeneous cancer stem cell (CSC) population within a tumor bulk is related to disease recurrence and therapy resistance. For this reason, CSC targeting presents a promising strategy for hampering cancer recurrence. Increasing evidence shows that NPs can inhibit crucial signaling pathways involved in the maintenance of CSC stemness and sensitize CSCs to standard chemotherapeutic treatments. Moreover, their limited toxicity and low costs for large-scale production could accelerate the use of NPs in clinical settings. In this review, we will summarize the most relevant studies regarding the effects of NPs derived from major natural sources, e.g., food, botanical, and marine species, on CSCs, elucidating their use in pre-clinical and clinical studies.
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Affiliation(s)
- Melania Lo Iacono
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Paola Bianca
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Ornella Roberta Brancato
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Giampaolo Muratore
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Narges Roozafzay
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Kimiya Shams
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Lorenzo Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Cristina Colarossi
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Viagrande, 95029 Catania, Italy
| | - Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
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21
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Mishra A, Pathak Y, Mishra SK, Prakash H, Tripathi V. Natural compounds as a potential modifier of stem cells renewal: Comparative analysis. Eur J Pharmacol 2022; 938:175412. [PMID: 36427534 DOI: 10.1016/j.ejphar.2022.175412] [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: 06/16/2022] [Revised: 11/09/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
Cancer stem cells (CSCs) are indispensable for development, progression, drug resistance, and tumor metastasis. Current cancer-directed interventions target targeting rapidly dividing cancer cells and slow dividing CSCs, which are the root cause of cancer origin and recurrence. The most promising targets include several self-renewal pathways involved in the maintenance and renewal of CSCs, such as the Wnt/β-Catenin, Sonic Hedgehog, Notch, Hippo, Autophagy, and Ferroptosis. In view of safety, natural compounds are coming to the front line of treatment modalities for modifying various signaling pathways simultaneously involved in maintaining CSCs. Therefore, targeting CSCs with natural compounds is a promising approach to treating various types of cancers. In view of this, here we provide a comprehensive update on the current status of natural compounds that effectively tune key self-renewal pathways of CSCs. In addition, we highlighted surface expression markers in several types of cancer. We also emphasize how natural compounds target these self-renewal pathways to reduce therapy resistance and cancer recurrence properties of CSCs, hence providing valuable cancer therapeutic strategies. The inclusion of nutraceuticals is believed to enhance the therapeutic efficacy of current cancer-directed interventions significantly.
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Affiliation(s)
- Amaresh Mishra
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201310, India
| | - Yamini Pathak
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201310, India
| | | | - Hridayesh Prakash
- Amity Institute of Virology and Immunology, Amity University, Uttar Pradesh, India
| | - Vishwas Tripathi
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201310, India.
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22
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Todosenko N, Yurova K, Khaziakhmatova O, Malashchenko V, Khlusov I, Litvinova L. Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells. Pharmaceutics 2022; 14:pharmaceutics14102181. [PMID: 36297616 PMCID: PMC9612132 DOI: 10.3390/pharmaceutics14102181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 11/23/2022] Open
Abstract
One of the main problems of modern health care is the growing number of oncological diseases both in the elderly and young population. Inadequately effective chemotherapy, which remains the main method of cancer control, is largely associated with the emergence of multidrug resistance in tumor cells. The search for new solutions to overcome the resistance of malignant cells to pharmacological agents is being actively pursued. Another serious problem is immunosuppression caused both by the tumor cells themselves and by antitumor drugs. Of great interest in this context is heparin, a biomolecule belonging to the class of glycosaminoglycans and possessing a broad spectrum of biological activity, including immunomodulatory and antitumor properties. In the context of the rapid development of the new field of “osteoimmunology,” which focuses on the collaboration of bone and immune cells, heparin and delivery systems based on it may be of intriguing importance for the oncotherapy of malignant bone tumors. Osteosarcoma is a rare but highly aggressive, chemoresistant malignant tumor that affects young adults and is characterized by constant recurrence and metastasis. This review describes the direct and immune-mediated regulatory effects of heparin and drug delivery systems based on it on the molecular mechanisms of (multiple) drug resistance in (onco) pathological conditions of bone tissue, especially osteosarcoma.
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Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Kristina Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
| | - Igor Khlusov
- Department of Morphology and General Pathology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia
- Correspondence:
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23
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Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance. Int J Mol Sci 2022; 23:ijms231810244. [PMID: 36142147 PMCID: PMC9499610 DOI: 10.3390/ijms231810244] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of β-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erβ. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.
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24
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Li J, Wei W, Lai Z, Lai KP. In silico studies reveal the anti-osteosarcoma targets and action mechanisms of resveratrol. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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25
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Hashem S, Ali TA, Akhtar S, Nisar S, Sageena G, Ali S, Al-Mannai S, Therachiyil L, Mir R, Elfaki I, Mir MM, Jamal F, Masoodi T, Uddin S, Singh M, Haris M, Macha M, Bhat AA. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed Pharmacother 2022; 150:113054. [PMID: 35658225 DOI: 10.1016/j.biopha.2022.113054] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs.
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Affiliation(s)
- Sheema Hashem
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Tayyiba Akbar Ali
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Sabah Akhtar
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | | | - Shahid Ali
- International Potato Center (CIP), Shillong, Meghalaya, India
| | - Sharefa Al-Mannai
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha, Qatar
| | - Rashid Mir
- Prince Fahd Bin Sultan Research chair, Department Of Medical Lab Technology, FAMS, University of Tabuk,Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Muzaffar Mir
- Department of Basic Medical Sciences, College of Medicine, University of Bisha, Saudi Arabia
| | - Farrukh Jamal
- Dr. Rammanohar Lohia Avadh University, Ayodhya, India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar; Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Muzafar Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Kashmir, India.
| | - Ajaz A Bhat
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar.
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26
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Almatroodi SA, A. Alsahli M, S. M. Aljohani A, Alhumaydhi FA, Babiker AY, Khan AA, Rahmani AH. Potential Therapeutic Targets of Resveratrol, a Plant Polyphenol, and Its Role in the Therapy of Various Types of Cancer. Molecules 2022; 27:2665. [PMID: 35566016 PMCID: PMC9101422 DOI: 10.3390/molecules27092665] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 12/17/2022] Open
Abstract
Cancer is among the most prominent causes of mortality worldwide. Different cancer therapy modes employed, including chemotherapy and radiotherapy, have been reported to be significant in cancer management, but the side effects associated with these treatment strategies are still a health problem. Therefore, alternative anticancer drugs based on medicinal plants or their active compounds have been generating attention because of their less serious side effects. Medicinal plants are an excellent source of phytochemicals that have been recognized to have health-prompting effects through modulating cell signaling pathways. Resveratrol is a well-known polyphenolic molecule with antioxidant, anti-inflammatory, and health-prompting effects among which its anticancer role has been best defined. Additionally, this polyphenol has confirmed its role in cancer management because it activates tumor suppressor genes, suppresses cell proliferation, induces apoptosis, inhibits angiogenesis, and modulates several other cell signaling molecules. The anticancer potential of resveratrol is recognized in numerous in vivo and in vitro studies. Previous experimental data suggested that resveratrol may be valuable in cancer management or improve the efficacy of drugs when given with anticancer drugs. This review emphasizes the potential role of resveratrol as an anticancer drug by modulating numerous cells signaling pathways in different types of cancer.
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Affiliation(s)
- Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Mohammed A. Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Abdullah S. M. Aljohani
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Fahad A. Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Ali Yousif Babiker
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia;
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (S.A.A.); (M.A.A.); (F.A.A.); (A.Y.B.)
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27
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Wang Z, Song Y, Zhang H, Yang Y, Zhang S, Wang W. Local anesthetic levobupivacaine inhibits stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression. Aging (Albany NY) 2022; 14:2793-2804. [PMID: 35333774 PMCID: PMC9004559 DOI: 10.18632/aging.203975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 12/03/2021] [Indexed: 11/25/2022]
Abstract
Osteosarcoma is the most prevalent bone cancer and accounts for over half of sarcomas. In this study, we identified that the treatment of levobupivacaine suppressed proliferation of osteosarcoma cells in vitro. The tumor xenograft analysis showed that levobupivacaine significantly repressed the osteosarcoma cell growth in the nude mice. The treatment of levobupivacaine improved the apoptosis rate and attenuated invasion and migration abilities of osteosarcoma cells. The sphere formation capabilities of osteosarcoma cells were repressed by levobupivacaine. The protein levels of Sox-2, Oct3/4, and Nanog were inhibited by the treatment of levobupivacaine in osteosarcoma cells. Regarding mechanism, we identified that levobupivacaine inhibited MAFB and KAT5 expression in osteosarcoma cells. We observed that lysine acetyltransferase 5 could enriched in the promoter region of MAF BZIP transcription factor B, while levobupivacaine treatment could repressed the enrichment. The suppression of KAT5 by siRNA repressed the enrichment of histone H3 acetylation at lysine 27 and RNA polymerase II on promoter of MAFB. The expression of MAFB was decreased by KAT5 knockdown in osteosarcoma cells. The expression of MAFB was repressed by levobupivacaine, while the overexpression of KAT5 could reverse the repression of MAFB. KAT5 contributes to the cell proliferation and stemness of osteosarcoma cells. The overexpression of KAT5 or MAFB could reverse levobupivacaine-attenuated cell proliferation and stemness of osteosarcoma cells. Therefore, we concluded that local anesthetic levobupivacaine inhibited stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression. Levobupivacaine may act as a potential therapeutic candidate for osteosarcoma by targeting cancer stem cells.
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Affiliation(s)
- Zhan Wang
- The First School of Clinical Medicine of Lanzhou University, Department of Orthopaedics, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China.,Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China
| | - Yuxin Song
- The First School of Clinical Medicine of Lanzhou University, Department of Orthopaedics, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China.,Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China
| | - Hui Zhang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China
| | - Yang Yang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China
| | - Suifeng Zhang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China
| | - Wenji Wang
- The First School of Clinical Medicine of Lanzhou University, Department of Orthopaedics, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China
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28
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De Luca A, Bellavia D, Raimondi L, Carina V, Costa V, Fini M, Giavaresi G. Multiple Effects of Resveratrol on Osteosarcoma Cell Lines. Pharmaceuticals (Basel) 2022; 15:342. [PMID: 35337142 PMCID: PMC8956103 DOI: 10.3390/ph15030342] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary bone sarcoma affecting the life of pediatric patients. The clinical treatment faces numerous difficulties, including the adverse effects of chemotherapies, chemoresistance, and recurrences. In this study, the effects of resveratrol (RSV), a natural polyphenol, on OS cell lines were investigated to evaluate its action as an adjuvant therapy to the current chemotherapy regimens. RSV exhibited multiple tumor-suppressing activities on OS cell lines, inducing a series of critical events. We found (1) a cell growth inhibition due to an increase in cell distress, which was, in part, due to the involvement of the AKT and caspase-3 pathways, (2) an increase in cellular differentiation due to major gene expression levels of the osteoblastic differentiation genes, (3) an inhibition of IL-6 secretion due to an epigenetic effect on the IL-6 promoter, and (4) an inhibition of OS cells migration related to the decrease in IL-8 secretion levels due to an epigenetic effect on its promoter. Finally, the cotreatment of RSV with doxorubicin and cisplatin increased their cytotoxic effect on OS cells. Although further investigations are mandatory, it seems RSV might be a promising therapeutic adjuvant agent for OS cell treatment, exerting an antitumor effect when combined with chemotherapy.
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Affiliation(s)
- Angela De Luca
- IRCCS Istituto Ortopedico Rizzoli, CS Surgical Sciences and Technologies—SS Omics Science Platform for Personalized Orthopedics, 40136 Bologna, Italy; (D.B.); (L.R.); (V.C.); (V.C.); (M.F.); (G.G.)
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29
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Rabelo ACS, Borghesi J, Noratto GD. The role of dietary polyphenols in osteosarcoma: A possible clue about the molecular mechanisms involved in a process that is just in its infancy. J Food Biochem 2021; 46:e14026. [PMID: 34873724 DOI: 10.1111/jfbc.14026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 12/11/2022]
Abstract
Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children, teenagers and young adults, being associated with early metastasis and poor prognosis. The beneficial effects of polyphenols have been investigated in different areas, including their potential to fight OS. Polyphenols are believed to reduce morbidity and/or slow down the development of cancer. This review aimed to assess the effect of polyphenols in OS and investigate their molecular mechanisms. It was observed that the broad spectrum of health-promoting properties of plant polyphenols in OS occurs mainly due to modulation of reactive oxygen species, anti-inflammatory activity, anti-angiogenesis, apoptosis inducer, inhibition of invasion and metastasis. However, it is worth mentioning that although the promising effects of polyphenols in the fight against OS, most of the studies have been performed using in vitro and in vivo animal models. Therefore, studies in humans are needed to validate the effectiveness of polyphenols in OS treatment. PRACTICAL APPLICATIONS: Polyphenols are widely used for various diseases, however, until now, their real role in the treatment of osteosarcoma remains unknown. This review provides a broad spectrum of research conducted with polyphenols and their potential as adjuvant therapy in the treatment of osteosarcoma. However, prior to their clinical application for osteosarcoma treatment, there is a need to isolate and identify specific polyphenolic compounds with high antitumor activity, increase their oral bioavailability, and to investigate their interactions with chemotherapeutic drugs being used in clinical practice.
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Affiliation(s)
- Ana Carolina Silveira Rabelo
- Department of Food and Experimental Nutrition, Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Jéssica Borghesi
- Department of Anatomy, Faculty of Veterinary Medicine and Animal Science, University of São Paulo (USP), São Paulo, Brazil
| | - Giuliana D Noratto
- Departament of Nutrition and Food Science, Texas A&M University, College Station, Texas, USA
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30
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Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies. Int J Mol Sci 2021; 22:ijms222111669. [PMID: 34769099 PMCID: PMC8584029 DOI: 10.3390/ijms222111669] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/23/2021] [Accepted: 10/23/2021] [Indexed: 02/07/2023] Open
Abstract
As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.
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31
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Tobeiha M, Rajabi A, Raisi A, Mohajeri M, Yazdi SM, Davoodvandi A, Aslanbeigi F, Vaziri M, Hamblin MR, Mirzaei H. Potential of natural products in osteosarcoma treatment: Focus on molecular mechanisms. Biomed Pharmacother 2021; 144:112257. [PMID: 34688081 DOI: 10.1016/j.biopha.2021.112257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma is the most frequent type of bone cancer found in children and adolescents, and commonly arises in the metaphyseal region of tubular long bones. Standard therapeutic approaches, such as surgery, chemotherapy, and radiation therapy, are used in the management of osteosarcoma. In recent years, the mortality rate of osteosarcoma has decreased due to advances in treatment methods. Today, the scientific community is investigating the use of different naturally derived active principles against various types of cancer. Natural bioactive compounds can function against cancer cells in two ways. Firstly they can act as classical cytotoxic compounds by non-specifically affecting macromolecules, such as DNA, enzymes, and microtubules, which are also expressed in normal proliferating cells, but to a greater extent by cancer cells. Secondly, they can act against oncogenic signal transduction pathways, many of which are activated in cancer cells. Some bioactive plant-derived agents are gaining increasing attention because of their anti-cancer properties. Moreover, some naturally-derived compounds can significantly promote the effectiveness of standard chemotherapy drugs, and in certain cases are able to ameliorate drug-induced adverse effects caused by chemotherapy. In the present review we summarize the effects of various naturally-occurring bioactive compounds against osteosarcoma.
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Affiliation(s)
- Mohammad Tobeiha
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Arash Raisi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahshad Mohajeri
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Fatemeh Aslanbeigi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - MohamadSadegh Vaziri
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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32
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Mierziak J, Kostyn K, Boba A, Czemplik M, Kulma A, Wojtasik W. Influence of the Bioactive Diet Components on the Gene Expression Regulation. Nutrients 2021; 13:3673. [PMID: 34835928 PMCID: PMC8619229 DOI: 10.3390/nu13113673] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Diet bioactive components, in the concept of nutrigenetics and nutrigenomics, consist of food constituents, which can transfer information from the external environment and influence gene expression in the cell and thus the function of the whole organism. It is crucial to regard food not only as the source of energy and basic nutriments, crucial for living and organism development, but also as the factor influencing health/disease, biochemical mechanisms, and activation of biochemical pathways. Bioactive components of the diet regulate gene expression through changes in the chromatin structure (including DNA methylation and histone modification), non-coding RNA, activation of transcription factors by signalling cascades, or direct ligand binding to the nuclear receptors. Analysis of interactions between diet components and human genome structure and gene activity is a modern approach that will help to better understand these relations and will allow designing dietary guidances, which can help maintain good health.
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Affiliation(s)
- Justyna Mierziak
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Kamil Kostyn
- Department of Genetics, Plant Breeding & Seed Production, Faculty of Life Sciences and Technology, Wroclaw University of Environmental and Life Sciences, pl. Grunwaldzki 24A, 50-363 Wroclaw, Poland;
| | - Aleksandra Boba
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Magdalena Czemplik
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Anna Kulma
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
| | - Wioleta Wojtasik
- Faculty of Biotechnology, University of Wrocław, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland; (A.B.); (M.C.); (A.K.)
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Mahadik N, Bhattacharya D, Padmanabhan A, Sakhare K, Narayan KP, Banerjee R. Targeting steroid hormone receptors for anti-cancer therapy-A review on small molecules and nanotherapeutic approaches. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 14:e1755. [PMID: 34541822 DOI: 10.1002/wnan.1755] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/11/2022]
Abstract
The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and context-specific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHR-targeted cancer nanotherapeutics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Namita Mahadik
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Dwaipayan Bhattacharya
- Department of Biological Sciences, Birla Institute of Technology Pilani, Hyderabad, India
| | - Akshaya Padmanabhan
- Department of Biological Sciences, Birla Institute of Technology Pilani, Hyderabad, India
| | - Kalyani Sakhare
- Department of Biological Sciences, Birla Institute of Technology Pilani, Hyderabad, India
| | - Kumar Pranav Narayan
- Department of Biological Sciences, Birla Institute of Technology Pilani, Hyderabad, India
| | - Rajkumar Banerjee
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
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Xiao Z, Passeri G, Northcote-Smith J, Singh K, Suntharalingam K. Osteosarcoma Stem Cell Potent Gallium(III)-Polypyridyl Complexes Bearing Diflunisal. Chemistry 2021; 27:13846-13854. [PMID: 34269487 PMCID: PMC8518360 DOI: 10.1002/chem.202102207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Indexed: 12/02/2022]
Abstract
We report the anti‐osteosarcoma stem cell (OSC) properties of a series of gallium(III)‐polypyridyl complexes (5‐7) containing diflunisal, a non‐steroidal anti‐inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8‐tetramethyl‐1,10‐phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase‐2 (COX‐2) and kills osteosarcoma cells in a COX‐2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase‐dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX‐2 and damaging nuclear DNA.
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Affiliation(s)
- Zhiyin Xiao
- School of Chemistry, University of Leicester, Leicester, UK.,College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, China
| | | | | | - Kuldip Singh
- School of Chemistry, University of Leicester, Leicester, UK
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35
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Targeting cancer stem cells by nutraceuticals for cancer therapy. Semin Cancer Biol 2021; 85:234-245. [PMID: 34273521 DOI: 10.1016/j.semcancer.2021.07.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.
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36
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Erkisa M, Sariman M, Geyik OG, Geyik CG, Stanojkovic T, Ulukay E. Natural Products as a Promising Therapeutic Strategy to Target Cancer Stem Cells. Curr Med Chem 2021; 29:741-783. [PMID: 34182899 DOI: 10.2174/0929867328666210628131409] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 11/22/2022]
Abstract
Cancer is still a deadly disease, and its treatment desperately needs to be managed in a very sophisticated way through fast-developing novel strategies. Most of the cancer cases eventually develop into recurrencies, for which cancer stem cells (CSCs) are thought to be responsible. They are considered as a subpopulation of all cancer cells of tumor tissue with aberrant regulation of self-renewal, unbalanced proliferation, and cell death properties. Moreover, CSCs show a serious degree of resistance to chemotherapy or radiotherapy and immune surveillance as well. Therefore, new classes of drugs are rushing into the market each year, which makes the cost of therapy increase dramatically. Natural products are also becoming a new research area as a diverse chemical library to suppress CSCs. Some of the products even show promise in this regard. So, the near future could witness the introduction of natural products as a source of new chemotherapy modalities, which may result in the development of novel anticancer drugs. They could also be a reasonably-priced alternative to highly expensive current treatments. Nowadays, considering the effects of natural compounds on targeting surface markers, signaling pathways, apoptosis, and escape from immunosurveillance have been a highly intriguing area in preclinical and clinical research. In this review, we present scientific advances regarding their potential use in the inhibition of CSCs and the mechanisms by which they kill the CSCs.
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Affiliation(s)
- Merve Erkisa
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Melda Sariman
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Oyku Gonul Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Caner Geyik Geyik
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
| | - Tatjana Stanojkovic
- Experimental Oncology Deparment, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Pasterova 14. Serbia
| | - Engin Ulukay
- Molecular Cancer Research Center (ISUMKAM), Istinye University, Istanbul, Turkey
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37
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Mu Q, Najafi M. Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells. Int Immunopharmacol 2021; 98:107895. [PMID: 34171623 DOI: 10.1016/j.intimp.2021.107895] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/09/2021] [Accepted: 06/13/2021] [Indexed: 12/17/2022]
Abstract
Tumor resistance to therapy modalities is one of the major challenges to the eradication of cancer cells and complete treatment. Tumor includes a wide range of cancer and non-cancer cells that play key roles in the proliferation of cancer cells and suppression of anti-tumor immunity. For overcoming tumor resistance to therapy, it is important to have in-depth knowledge relating to intercellular communications within the tumor microenvironment (TME). TME includes various types of immune cells such as CD4 + T lymphocytes, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, macrophages, and T regulatory cells (Tregs). Furthermore, some non-immune cells like cancer stem cells (CSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs) are involved in the promotion of tumor growth. The interactions between these cells with cancer cells play a key role in tumor growth or inhibition. Resveratrol as a natural agent has shown the ability to modulate the immune system to potentiate anti-tumor immunity and also help to attenuate cancer cells and CSCs resistance. Thus, this review explains how resveratrol can modulate interactions within TME.
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Affiliation(s)
- Qi Mu
- College of Nursing, Inner Mongolia University for Nationalities, Tongliao 028000, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Gairola K, Gururani S, Bahuguna A, Garia V, Pujari R, Dubey SK. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. J Food Biochem 2021; 45:e13772. [PMID: 34028051 DOI: 10.1111/jfbc.13772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022]
Abstract
Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.
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Affiliation(s)
- Kanchan Gairola
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shriya Gururani
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Ananya Bahuguna
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Vaishali Garia
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Rohit Pujari
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shiv K Dubey
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
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Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy. Molecules 2021; 26:molecules26041109. [PMID: 33669817 PMCID: PMC7922180 DOI: 10.3390/molecules26041109] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/13/2021] [Accepted: 02/16/2021] [Indexed: 12/29/2022] Open
Abstract
Despite the recent advances in the field of chemically synthetized pharmaceutical agents, nature remains the main supplier of bioactive molecules. The research of natural products is a valuable approach for the discovery and development of novel biologically active compounds possessing unique structures and mechanisms of action. Although their use belongs to the traditional treatment regimes, plant-derived compounds still cover a large portion of the current-day pharmaceutical agents. Their medical importance is well recognized in the field of oncology, especially as an alternative to the limitations of conventional chemotherapy (severe side effects and inefficacy due to the occurrence of multi-drug resistance). This review offers a comprehensive perspective of the first blockbuster chemotherapeutic agents of natural origin’s (e.g. taxol, vincristine, doxorubicin) mechanism of action using 3D representation. In addition is portrayed the step-by-step evolution from preclinical to clinical evaluation of the most recently studied natural compounds with potent antitumor activity (e.g. resveratrol, curcumin, betulinic acid, etc.) in terms of anticancer mechanisms of action and the possible indications as chemotherapeutic or chemopreventive agents and sensitizers. Finally, this review describes several efficient platforms for the encapsulation and targeted delivery of natural compounds in cancer treatment
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40
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Liu Y, Liao S, Bennett S, Tang H, Song D, Wood D, Zhan X, Xu J. STAT3 and its targeting inhibitors in osteosarcoma. Cell Prolif 2020; 54:e12974. [PMID: 33382511 PMCID: PMC7848963 DOI: 10.1111/cpr.12974] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/21/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is one of seven STAT family members involved with the regulation of cellular growth, differentiation and survival. STAT proteins are conserved among eukaryotes and are important for biological functions of embryogenesis, immunity, haematopoiesis and cell migration. STAT3 is widely expressed and located in the cytoplasm in an inactive form. STAT3 is rapidly and transiently activated by tyrosine phosphorylation by a range of signalling pathways, including cytokines from the IL‐6 family and growth factors, such as EGF and PDGF. STAT3 activation and subsequent dimer formation initiates nuclear translocation of STAT3 for the regulation of target gene transcription. Four STAT3 isoforms have been identified, which have distinct biological functions. STAT3 is considered a proto‐oncogene and constitutive activation of STAT3 is implicated in the development of various cancers, including multiple myeloma, leukaemia and lymphomas. In this review, we focus on recent progress on STAT3 and osteosarcoma (OS). Notably, STAT3 is overexpressed and associated with the poor prognosis of OS. Constitutive activation of STAT3 in OS appears to upregulate the expression of target oncogenes, leading to OS cell transformation, proliferation, tumour formation, invasion, metastasis, immune evasion and drug resistance. Taken together, STAT3 is a target for cancer therapy, and STAT3 inhibitors represent potential therapeutic candidates for the treatment of OS.
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Affiliation(s)
- Yun Liu
- Department of Spine and Osteopathic Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.,Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Shijie Liao
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China.,Department of Trauma Orthopedic and Hand Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Samuel Bennett
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Haijun Tang
- Department of Orthopedic, Guangxi hospital for nationalities, Nanning, Guangxi, China
| | - Dezhi Song
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - David Wood
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Xinli Zhan
- Department of Spine and Osteopathic Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.,Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiake Xu
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
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41
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Kharkar PS. Cancer Stem Cell (CSC) Inhibitors in Oncology-A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives. J Med Chem 2020; 63:15279-15307. [PMID: 33325699 DOI: 10.1021/acs.jmedchem.0c01336] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.
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Affiliation(s)
- Prashant S Kharkar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
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42
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Bhaskara VK, Mittal B, Mysorekar VV, Amaresh N, Simal-Gandara J. Resveratrol, cancer and cancer stem cells: A review on past to future. Curr Res Food Sci 2020; 3:284-295. [PMID: 33305295 PMCID: PMC7718213 DOI: 10.1016/j.crfs.2020.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer remains to be an unresolved medical challenge despite of tremendous advancement in basic science research and clinical medicine. One of the major limitations is due to the side effects of chemotherapy which remains to be palliative without offering any permanent cure for cancer. Cancer stem cells (CSCs) are the subpopulation of cells in tumors that remain viable even after surgery, chemo- and radio-therapy that eventually responsible for tumor relapse. Hence, by eliminating non-stem cancer cells and cancer stem cells from the patient, permanent cure is expected. Phytochemicals have been under the intensive study to target these CSCs effectively and permanently as they do not cause any side effects. Resveratrol (RSV) is one such compound attaining lot of interest in recent days to target CSCs either alone or in combination. RSV has been used by several researchers to target cancer cells in a variety of disease models, however its CSC targeting abilities are under intensive study at present. This review is to summarize the effects of RSV under in vitro and in vivo conditions along with advantages and disadvantages of its uses against cancer cells and cancer stem cells. From the first reports on phytochemical applications against cancer and cancer stem cells in 1997 and 2002 respectively followed by later reports, up to date observations and developments are enlisted from PubMed in this comprehensive review. RSV is shown to be a potential compound having impact on altering the signal transduction pathways in cancer cells. However, the effects are variable under in vitro and in vivo conditions, and also with its use alone or in combination with other small molecules. Past research on RSV is emphasizing the importance of in vivo experimental models and clinical trials with different prospective combinations, is a hope for future promising treatment regimen.
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Affiliation(s)
- Vasanth K Bhaskara
- Department of Biochemistry-PG, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India
| | - Bharti Mittal
- Immuniteit Lab Pvt Ltd., Electronic City, Bengaluru 560024, India
| | - Vijaya V Mysorekar
- Department of Pathology, Ramaiah Medical College & Hospitals (RMCH), Bengaluru 560054, India
| | - Nagarathna Amaresh
- Department of Biotechnology, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E32004 Ourense, Spain
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Lv T, Jian Z, Li D, Ao R, Zhang X, Yu B. Oxyresveratrol induces apoptosis and inhibits cell viability via inhibition of the STAT3 signaling pathway in Saos‑2 cells. Mol Med Rep 2020; 22:5191-5198. [PMID: 33174060 PMCID: PMC7646976 DOI: 10.3892/mmr.2020.11591] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Oxyresveratrol (ORES) is a natural phenolic compound with multiple biological functions including antioxidation, anti-inflammation and neuroprotection; however, the inhibitory effect of ORES on osteosarcoma remains largely unknown. The present study aimed to determine the effects of ORES on osteosarcoma cell Saos-2. Cell Counting Kit-8 assay was performed to detect Soas-2 cell viability. Annexin-FITC/PI staining and JC-1 staining were used to measure cell apoptosis and the change of mitochondrial membrane potential. In addition, western blotting was conducted to determine the expression levels of apoptotic proteins and the phosphorylation of STAT3. It was found that ORES inhibited cell viability and induced apoptosis of osteosarcoma Saos-2 cells in a concentration-dependent manner. In addition, ORES increased the expression levels of apoptotic proteases caspase-9 and caspase-3 and reduced mitochondrial membrane potential. In response to ORES treatment, the expression levels of pro-apoptotic proteins, Bad and Bax, were enhanced, whereas those of anti-apoptotic proteins, Bcl-2 and Bcl-xL, were reduced. In addition, the phosphorylation of STAT3 was attenuated in Saos-2 cells after treatment with ORES. Inhibition of cell viability and apoptosis induction by ORES were rescued by enhancement of STAT3 activation upon treatment with IL-6. Collectively, the present study indicated that ORES induced apoptosis and inhibited cell viability, which may be associated with the inhibition of STAT3 activation; thus, ORES represents a promising agent for treating osteosarcoma.
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Affiliation(s)
- Tao Lv
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Zhen Jian
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Dejian Li
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Rongguang Ao
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Xu Zhang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Baoqing Yu
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
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Sun X, Xu Q, Zeng L, Xie L, Zhao Q, Xu H, Wang X, Jiang N, Fu P, Sang M. Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3 Tyr705 phosphorylation. Cancer Med 2020; 9:8685-8700. [PMID: 33040485 PMCID: PMC7666735 DOI: 10.1002/cam4.3510] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/17/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022] Open
Abstract
Aberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES‐mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial‐mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway.
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Affiliation(s)
- Xiaodong Sun
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Qianqian Xu
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Lian Zeng
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Lixia Xie
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Qiang Zhao
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Hongxia Xu
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Xuanbin Wang
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Nan Jiang
- Hubei Province Hospital of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, People's Republic of China
| | - Pan Fu
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Ming Sang
- Hubei Institute of Parkinson's Disease at Xiangyang No. 1 People's Hospital, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, People's Republic of China
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45
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The Potential of Phytochemicals in Oral Cancer Prevention and Therapy: A Review of the Evidence. Biomolecules 2020; 10:biom10081150. [PMID: 32781654 PMCID: PMC7465709 DOI: 10.3390/biom10081150] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/29/2020] [Accepted: 08/03/2020] [Indexed: 12/15/2022] Open
Abstract
The etiological factors of oral cancer are complex including drinking alcohol, smoking tobacco, betel quid chewing, human papillomavirus infection, and nutritional deficiencies. Understanding the molecular mechanism of oral cancer is vital. The traditional treatment for patients with oral squamous cell carcinoma (e.g., surgery, radiotherapy, and chemotherapy) and targeted molecular therapy still have numerous shortcomings. In recent years, the use of phytochemical factors to prevent or treat cancer has received increasing attention. These phytochemicals have little or no toxicity against healthy tissues and are thus ideal chemopreventive agents. However, phytochemicals usually have low water solubility, low bioavailability, and insufficient targeting which limit therapeutic use. Numerous studies have investigated the development of phytochemical delivery systems to address these problems. The present article provides an overview of oral cancer including the etiological factors, diagnosis, and traditional therapy. Furthermore, the classification, dietary sources, anticancer bioactivity, delivery system improvements, and molecular mechanisms against oral cancer of phytochemicals are also discussed in this review.
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46
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Sin ZW, Bhardwaj V, Pandey AK, Garg M. A brief overview of antitumoral actions of bruceine D. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:200-217. [PMID: 36046775 PMCID: PMC9400783 DOI: 10.37349/etat.2020.00013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/30/2020] [Indexed: 12/25/2022] Open
Abstract
Cancer remains the second leading cause of mortality globally. In combating cancer, conventional chemotherapy and/or radiotherapy are administered as first-line therapy. However, these are usually accompanied with adverse side effects that decrease the quality of patient’s lives. As such, natural bioactive compounds have gained an attraction in the scientific and medical community as evidence of their anticancer properties and attenuation of side effects mounted. In particular, quassinoids have been found to exhibit a plethora of inhibitory activities such as anti-proliferative effects on tumor development and metastasis. Recently, bruceine D, a quassinoid isolated from the shrub Brucea javanica (L.) Merr. (Simaroubaceae), has come under immense investigation on its antineoplastic properties in various human cancers including pancreas, breast, lung, blood, bone, and liver. In this review, we have highlighted the antineoplastic effects of bruceine D and its mode of actions in different tumor models.
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Affiliation(s)
- Zi Wayne Sin
- Department of Biological Sciences, National University of Singapore, Singapore 117600, Singapore
| | - Vipul Bhardwaj
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Manesar, Haryana 122413, India
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India
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Eskandari A, Flamme M, Xiao Z, Suntharalingam K. The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis-Inducing Nickel(II)-Phenanthroline Complex. Chembiochem 2020; 21:2854-2860. [PMID: 32415808 DOI: 10.1002/cbic.202000231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/14/2020] [Indexed: 12/26/2022]
Abstract
We report the anti-osteosarcoma and anti-osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1. Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two- and three-dimensional osteosarcoma cell cultures. Mechanistic studies revealed that 1 induces osteosarcoma cell death by necroptosis, an ordered form of necrosis. The nickel(II) complex, 1 triggers necrosome-dependent mitrochondrial membrane depolarisation and propidium iodide uptake. Interestingly, 1 does not evoke necroptosis by elevating intracellular reactive oxygen species (ROS) or hyperactivation of poly ADP ribose polymerase (PARP-1). ROS elevation and PARP-1 activity are traits that have been observed for established necroptosis inducers such as shikonin, TRAIL and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our knowledge, this is the first report into the anti-osteosarcoma and anti-OSC properties of a nickel complex.
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Affiliation(s)
- Arvin Eskandari
- School of Pharmacy, University College London, London, WC1N 1AX, UK
| | - Marie Flamme
- Department of Structural Biology and Chemistry, Institut Pasteur, Paris, 75015, France
| | - Zhiyin Xiao
- School of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
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Mohan CD, Rangappa S, Preetham HD, Chandra Nayaka S, Gupta VK, Basappa S, Sethi G, Rangappa KS. Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature. Semin Cancer Biol 2020; 80:157-182. [DOI: 10.1016/j.semcancer.2020.03.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 02/07/2023]
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Robin P, Singh K, Suntharalingam K. Gallium(iii)-polypyridyl complexes as anti-osteosarcoma stem cell agents. Chem Commun (Camb) 2020; 56:1509-1512. [PMID: 31917383 DOI: 10.1039/c9cc08962d] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Gallium(iii) complexes with polypridyl ligands are shown to kill bulk osteosarcoma cells and osteosarcoma stem cells (OSCs) with up to nanomolar potency. The most effective complex induces apoptosis in osteosarcoma cells by damaging genomic DNA. To the best of our knowledge this is the first investigation into metal-based anti-OSC agents.
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Affiliation(s)
- Perrine Robin
- School of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
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50
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Revisiting the development of small molecular inhibitors that directly target the signal transducer and activator of transcription 3 (STAT3) domains. Life Sci 2020; 242:117241. [DOI: 10.1016/j.lfs.2019.117241] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/19/2019] [Accepted: 12/26/2019] [Indexed: 12/31/2022]
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