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Pandey P, Ramniwas S, Pandey S, Lakhanpal S, Ballal S, Kumar S, Bhat M, Sharma S, Kumar MR, Khan F. Elucidating the anticancerous efficacy of genistein via modulating HPV (E7 and E6) oncogenes expression and apoptotic induction in cervical cancer cells. Biotechnol Appl Biochem 2025; 72:709-717. [PMID: 39491824 DOI: 10.1002/bab.2691] [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: 07/23/2024] [Accepted: 10/16/2024] [Indexed: 11/05/2024]
Abstract
In recent years, genistein has garnered increased interest for its ability to inhibit numerous deregulated targets associated with cancer progression and induction of programmed cell death and antiproliferative activities in human carcinoma cells. Cancer etiology is influenced via multiple disrupted signaling pathways. This study therefore directed toward investigating genistein efficacy in modulating mRNA expression levels of two crucial Human Pappiloma Virus (HPV) (E7 and E6) oncogenes for cancer treatment. Moreover, the inhibitory effects of genistein for HPV (E7 and E6) oncogenes in cervical carcinoma have not yet been reported. Current study investigated inhibitory potential of genistein in HPV (E7 and E6) oncogenes in HeLa cells. These oncogenes are known to deactivate many tumor suppressor proteins (p53 and pRB). Genistein therapy resulted in decreased cell proliferation and increased cell accumulation in the G (G0/G1) phase in HeLa cell lines. In addition, genistein therapy has resulted in the suppression of HPV (E7 and E6) gene expression and simultaneously increasing expression levels of p53 and pRB mRNA levels. As a consequence, there has been an activation of a series of caspases (3, 8, and 9), resulting in their cleavage. Consequently, our data suggests that genistein could be a powerful candidate for treating cervical cancer by targeting two important oncogenes involved in viral development. However, more in vitro research on primary cervical cancer cells is required to validate the clinically relevant efficacy of genistein against cervical cancer.
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Affiliation(s)
- Pratibha Pandey
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering & Technology, Chitkara University, Rajpura, Punjab, India
- Chitkara Centre for Research and Development, Chitkara University, Baddi, Himachal Pradesh, India
| | - Seema Ramniwas
- University Centre of Research and Development, University institute of Biotechnology, Chandigarh University, Gharuan, Mohali, Punjab, India
| | - Shivam Pandey
- School of Applied and Life Sciences, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Sanjay Kumar
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - Mahakshit Bhat
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, Rajasthan, India
| | - Shilpa Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, India
| | - Fahad Khan
- Center for Global Health Research Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Chennai, India
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Chen S, Huang H, Li Q, Cai J, Miao Z, Xie P, Tang S, He D. Carrier-free nanoparticles based on self-assembly of 5-FU and copper-genistein complexes for the combined treatment of hepatocellular carcinoma. Drug Deliv Transl Res 2025; 15:1299-1316. [PMID: 39126575 DOI: 10.1007/s13346-024-01676-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
5-Fluorouracil (5-FU) is commonly used as a chemotherapeutic drug for advanced HCC. However, the effectiveness of 5-FU is limited by the emergence of resistance and poor targeting efficiency. Combining 5-FU with natural compounds has shown promise in HCC treatment. In this study, we prepared carrier-free nanoparticles (GEN-Cu-GEN@FUA) containing 5-FU and genistein (GEN) in a synergistic ratio via a green synthesis procedure. The resulting GEN-Cu-GEN@FUA nanoparticles had a spherical or near spherical shape, a dynamic size of 129.3 ± 40.1 nm, and a high drug loading content of approximately 21.40% (5-FU) and 61.48% (GEN). These nanoparticles exhibited approximately 3.6-fold lower IC50 value than 5-FU alone in Bel-7402 cells and resulted in a 3.7-fold greater reduction in tumor weight compared to 5-FU alone in Bel-7402 tumor-bearing BALB/c mice. Importantly, the nanoparticles showed negligible systemic toxicity due to their synergistic effect on cancer cell dysfunction and significant amplification of intracellular glutathione consumption. Our findings suggest that the developed carrier-free nanomedicines offer a highly promising platform for the co-delivery of genistein (GEN) copper(II) complexes and 5-FU, with easy fabrication and great potential for clinical translation in HCC synergistic therapy.
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Affiliation(s)
- Siwei Chen
- Miluo Maternity and Child Care Hospital, Yueyang, Hunan Province, China
| | - Hongwu Huang
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
| | - Qi Li
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
| | - Jia Cai
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
| | - Zhuolin Miao
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systemy, Huaihua, Hunan, China
| | - Peikang Xie
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systemy, Huaihua, Hunan, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systemy, Huaihua, Hunan, China.
| | - Dongxiu He
- Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China.
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Li H, Dai Y, Wu D, Gao S, Guo J, Zhang P, Chen H, Kou F, Liu S, Feng A, Liu B, Hou D, Zhu X. Integrated multi-omics demonstrates enhanced antitumor efficacy of donafenib combined with FADS2 inhibition in hepatocellular carcinoma. Transl Oncol 2025; 51:102142. [PMID: 39550887 PMCID: PMC11615612 DOI: 10.1016/j.tranon.2024.102142] [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: 06/12/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 11/19/2024] Open
Abstract
Pharmacotherapy is crucial for advanced hepatocellular carcinoma (HCC). The multi-kinase inhibitor donafenib offers superior survival benefits over sorafenib. Donafenib has first-line status, but there is limited research for combination therapies with this anticancer agent. This study aimed to delineate donafenib's antitumor effects, including transcriptomics and proteomics to characterize gene expression changes in donafenib-treated HCC cell lines. In vitro and in vivo tumorigenicity studies were conducted to evaluate the combined antitumor effects of donafenib. Proteomic and transcriptomic analyses identified that donafenib downregulated fatty acid desaturase 2 (FADS2) at the protein and mRNA levels. In vitro and in vivo assays revealed an inhibitory effect of FADS2 blockade on HCC cell malignancy. The combination of donafenib and the FADS2 inhibitor sc-26,196 produced synergistic antitumor action, enhancing therapeutic efficacy in HCC cell lines and xenografted tumors in nude mice. These findings highlight the potential of FADS2 as a biomarker for HCC and show a promising combinatorial therapy for its treatment. Thus, we provide a theoretical basis for translating laboratory research into clinical applications.
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Affiliation(s)
- Hui Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Yafeng Dai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Di Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Song Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Jianhai Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Pengjun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Hui Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Fuxin Kou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Shaoxing Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Aiwei Feng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Baojiang Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Dongdong Hou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Xu Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, PR China.
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4
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Arzuk E, Armağan G. Genistein and daidzein induce ferroptosis in MDA-MB-231 cells. J Pharm Pharmacol 2024; 76:1599-1608. [PMID: 39245043 DOI: 10.1093/jpp/rgae106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 07/25/2024] [Indexed: 09/10/2024]
Abstract
OBJECTIVES In recent years, there has been a growing interest in targeting ferroptosis for the treatment and prevention of multiple cancers. This study aimed to assess the contribution of ferroptosis to the antiproliferative effects of genistein (GN) and daidzein (DZ) in breast cancer cell lines. METHODS MDA-MB-231 and MCF-7 cells were employed as an in vitro model. The antiproliferative effects of GN and DZ were determined by WST-1 assay in the presence of specific inhibitors of different cell death pathways. The mRNA expressions of Gpx4 and Fsp-1, the levels of lipid peroxidation, glutathione (GSH)/glutathione disulfide (GSSG) ratio, and intracellular iron ion content were assessed in GN- or DZ-treated cells. RESULTS GN and DZ were found to cause ferroptotic cell death in MDA-MB-231, as confirmed by the reversal of viability when cells were pretreated with ferrostatin-1. Furthermore, both phytochemicals induced biochemical markers of ferroptosis, including lipid peroxidation and iron ions levels, and decreased GSH/GSSG levels. The mRNA expression levels of the main anti-ferroptotic genes, Gpx4 and Fsp-1, were diminished by the treatment of both phytochemicals. Surprisingly, ferroptosis did not play a role in GN- or DZ-induced cell death in MCF-7 cells. CONCLUSION Our findings highlight the potential of GN and DZ as ferroptosis inducers in triple-negative breast cancer cells.
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Affiliation(s)
- Ege Arzuk
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35080, İzmir, Turkey
| | - Güliz Armağan
- Department of Biochemistry, Faculty of Pharmacy, Ege University, 35080, İzmir, Turkey
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Hon KW, Naidu R. Synergistic Mechanisms of Selected Polyphenols in Overcoming Chemoresistance and Enhancing Chemosensitivity in Colorectal Cancer. Antioxidants (Basel) 2024; 13:815. [PMID: 39061884 PMCID: PMC11273411 DOI: 10.3390/antiox13070815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Despite significant advances in medical treatment, chemotherapy as monotherapy can lead to substantial side effects and chemoresistance. This underscores the need for 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. Polyphenols represent a diverse group of natural compounds that can target multiple signaling pathways in cancer cells to induce anti-cancer effects. Additionally, polyphenols have been shown to work synergistically with chemotherapeutics and other natural compounds in cancer cells. This review aims to provide a comprehensive insight into the synergistic mechanisms of selected polyphenols as chemosensitizers in CRC cells. Further research and clinical trials are warranted to fully harness the synergistic mechanisms of selected polyphenols combined with chemotherapy or natural compounds in improving cancer treatment outcomes.
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Affiliation(s)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;
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Hossein Karami M, Abdouss M. Cutting-edge tumor nanotherapy: Advancements in 5-fluorouracil Drug-loaded chitosan nanoparticles. INORG CHEM COMMUN 2024; 164:112430. [DOI: 10.1016/j.inoche.2024.112430] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Rodrigues P, Bangali H, Hammoud A, Mustafa YF, Al-Hetty HRAK, Alkhafaji AT, Deorari MM, Al-Taee MM, Zabibah RS, Alsalamy A. COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Med Oncol 2024; 41:41. [PMID: 38165473 DOI: 10.1007/s12032-023-02256-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/15/2023] [Indexed: 01/03/2024]
Abstract
Cyclooxygenase (COX) enzymes are pivotal in inflammation and cancer development. COX-2, in particular, has been implicated in tumor growth, angiogenesis, and immune evasion. Recently, COX-2 inhibitors have arisen as potential therapeutic agents in cancer treatment. In addition, combining COX inhibitors with other treatment modalities has demonstrated the potential to improve therapeutic efficacy. This review aims to investigate the effects of COX inhibition, both alone and in combination with other methods, on signaling pathways and carcinogenesis in various cancers. In this study, a literature search of all major academic databases was conducted (PubMed, Scholar google), including the leading research on the mechanisms of COX-2, COX-2 inhibitors, monotherapy with COX-2 inhibitors, and combining COX-2-inhibitors with chemotherapeutic agents in tumors. The study encompasses preclinical and clinical evidence, highlighting the positive findings and the potential implications for clinical practice. According to preclinical studies, multiple signaling pathways implicated in tumor cell proliferation, survival, invasion, and metastasis can be suppressed by inhibiting COX. In addition, combining COX inhibitors with chemotherapy drugs, targeted therapies, immunotherapies, and miRNA-based approaches has enhanced anti-tumor activity. These results suggest that combination therapy has the potential to overcome resistance mechanisms and improve treatment outcomes. However, caution must be exercised when selecting and administering combination regimens. Not all combinations of COX-2 inhibitors with other drugs result in synergistic effects; some may even have unfavorable interactions. Therefore, personalized approaches that consider the specific characteristics of the cancer and the medications involved are crucial for optimizing therapeutic strategies. In conclusion, as monotherapy or combined with other methods, COX inhibition bears promise in modulating signaling pathways and inhibiting carcinogenesis in various cancers. Additional studies and well-designed clinical trials are required to completely elucidate the efficacy of COX inhibition and combination therapy in enhancing cancer treatment outcomes. This narrative review study provides a detailed summary of COX-2 monotherapy and combination targeted therapy in cancer treatment.
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Affiliation(s)
- Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Harun Bangali
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia
| | - Ahmad Hammoud
- Department of Medical and Technical Information Technology, Bauman Moscow State Technical University, Moscow, Russia.
- Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Mishref Campus, Mubarak Al-Abdullah, Kuwait.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | | | | | - Maha Medha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | | | - Rahman S Zabibah
- College of Medical Technique, the Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
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Kumar V, Haldar S, Saini S, Ghosh S, Dhankhar P, Roy P. Pterostilbene-isothiocyanate reduces miR-21 level by impeding Dicer-mediated processing of pre-miR-21 in 5-fluorouracil and tamoxifen-resistant human breast cancer cell lines. 3 Biotech 2023; 13:193. [PMID: 37205177 PMCID: PMC10185726 DOI: 10.1007/s13205-023-03582-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 04/23/2023] [Indexed: 05/21/2023] Open
Abstract
Converging evidences identifies that microRNA-21 (miR-21) is responsible for drug resistance in breast cancer. This study aims to evaluate the miR-21-modulatory potential of a hybrid compound, pterostilbene-isothiocyanate (PTER-ITC), in tamoxifen-resistant MCF-7 (TR/MCF-7) and 5-fluorouracil-resistant MDA-MB 231 (5-FUR/MDA-MB 231) breast cancer cell lines, established by repeated exposure to gradually increasing the concentrations of tamoxifen and 5-fluorouracil, respectively. The outcome of this study shows that PTER-ITC effectively reduced the TR/MCF-7 (IC50: 37.21 µM) and 5-FUR/MDA-MB 231 (IC50: 47.00 µM) cell survival by inducing apoptosis, inhibiting cell migration, colony and spheroid formations in TR/MCF-7 cells, and invasiveness of 5-FUR/MDA-MB 231 cells. Most importantly, PTER-ITC significantly reduced the miR-21 expressions in these resistant cell lines. Moreover, the downstream tumor suppressor target gene of miR-21 such as PTEN, PDCD4, TIMP3, TPM1, and Fas L were upregulated after PTER-ITC treatment, as observed from transcriptional (RT-qPCR) and translational (immunoblotting) data. In silico and miR-immunoprecipitation (miR-IP) results showed reduced Dicer binding to pre-miR-21, after PTER-ITC treatment, indicating inhibition of miR-21 biogenesis. Collectively, the significance of this study is indicated by preliminary evidence for miR-21-modulatory effects of PTER-ITC that highlights the potential of this hybrid compound as an miR-21-targeting therapeutic agent.
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Affiliation(s)
- Viney Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
| | - Swati Haldar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
- Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand India
- Present Address: Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, Uttarakhand India
| | - Saakshi Saini
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
| | - Souvik Ghosh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
- Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand India
| | - Poonam Dhankhar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
- Present Address: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA USA
| | - Partha Roy
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247 667 India
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Emerging potential of 5-Fluorouracil-loaded chitosan nanoparticles in cancer therapy. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104371] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
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10
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AFROZE N, SUNDARAM MK, RAINA R, JATHAN J, BHAGAVATULA D, HAQUE S, HUSSAIN A. Concurrent treatment of flavonol with chemotherapeutics potentiates or counteracts the therapeutic implications in cervical cancer cells. MINERVA BIOTECHNOLOGY AND BIOMOLECULAR RESEARCH 2023. [DOI: 10.23736/s2724-542x.22.02938-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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Abstract
Flavonoids are polyphenolic phytochemicals, which occur naturally in plants and possess both anti-oxidant and pro-oxidant properties. Flavonoids are gaining increasing popularity in the pharmaceutical industry as healthy and cost-effective compounds. Flavonoids show beneficial pharmacological activities in the treatment and prevention of various types of diseases. They are natural and less toxic agents for cancer chemotherapy and radiotherapy via regulation of multiple cell signaling pathways and pro-oxidant effects. In this review, we have summarized the mechanisms of action of selected flavonoids, and their pharmacological implications and potential therapeutic applications in cancer therapy.
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Affiliation(s)
- Prabha Tiwari
- Riken Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Kaushala Prasad Mishra
- Ex Bhabha Atomic Research Center, Foundation for Education and Research, Mumbai, Maharashtra, India
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Flavonoids' Dual Benefits in Gastrointestinal Cancer and Diabetes: A Potential Treatment on the Horizon? Cancers (Basel) 2022; 14:cancers14246073. [PMID: 36551558 PMCID: PMC9776408 DOI: 10.3390/cancers14246073] [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: 11/13/2022] [Revised: 12/08/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients' lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.
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Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells. Pharmaceuticals (Basel) 2022; 15:ph15101299. [PMID: 36297411 PMCID: PMC9606943 DOI: 10.3390/ph15101299] [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: 08/08/2022] [Revised: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022] Open
Abstract
A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations.
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Kim DY, Park S, Yun J, Jang W, Rethineswaran VK, Van LTH, Giang LTT, Choi J, Lim HJ, Kwon SM. Oleuropein induces apoptosis in colorectal tumor spheres via mitochondrial fission. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00260-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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15
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Chen L, Lan J, Li Z, Zeng R, Wang Y, Zhen L, Jin H, Ding Y, Zhang T. A Novel Diosgenin-Based Liposome Delivery System Combined with Doxorubicin for Liver Cancer Therapy. Pharmaceutics 2022; 14:1685. [PMID: 36015311 PMCID: PMC9416271 DOI: 10.3390/pharmaceutics14081685] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022] Open
Abstract
As a malignant tumor, liver cancer is mainly treated with chemotherapy, while chemotherapeutic drugs, such as doxorubicin (DOX), may lead to toxicity, drug resistance and poor prognosis. The targeted delivery systems of combining natural products and chemotherapeutic drugs are useful to eliminate cancers with reduced toxicity and increased efficiency. In this study, a diosgenin-based liposome loaded with DOX (Dios-DOX-LP) was developed for synergistic treatment of liver cancer, in which Dios not only replaced cholesterol as the membrane regulator to keep stability of liposomes, but also became the chemotherapy adjuvant of DOX for synergistic treatment. Dios-DOX-LP was characterized by particle size (99.4 ± 6.2 nm), zeta potential (-33.3 ± 2.5 mV), and entrapment efficiency (DOX: 98.77 ± 2.04%, Dios: 87.75 ± 2.93%), which had a good stability and slow-release effect. Compared with commercial DOX liposome (CHOL-DOX-LP), Dios-DOX-LP had an improved anti-tumor effect in vitro and in vivo by inducing the apoptosis and inhibiting the proliferation of the tumor cell, which was 1.6 times better than CHOL-DOX-LP in cytotoxicity, and had 78% of the tumor inhibition rate on tumor-bearing nude mice. Dios-DOX-LP provided a novel idea to achieve synergistic tumor treatment using diosgenin as a liposome material.
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Affiliation(s)
- Lixia Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinshuai Lan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhe Li
- Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ruifeng Zeng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lu Zhen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Haojieyin Jin
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue Ding
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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16
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Ardıl B, Alper M. Potential cancer treatment effects of brusatol or eriodictyol combined with 5-fluorouracil (5-FU) in colorectal cancer cell. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1109-1123. [PMID: 35857038 DOI: 10.1007/s00210-022-02270-y] [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: 05/25/2022] [Accepted: 07/07/2022] [Indexed: 10/17/2022]
Abstract
Colorectal cancer is among the most frequently diagnosed cancers in patients today. In the treatment of this disease, combination or multicomponent therapy has been identified as a potential method to improve patient response and delay side effects. The aim of this study was to determine the effects on cell viability of commercial Bru and Erio used together with the anticancer drug 5-FU in the human colorectal cancer (CRC) cell line (HT-29 cell line) for the first time, as far as can be determined from available literature at this time. Additionally, the research seeks to study any potential effects on apoptosis. For this purpose, the effects of independent and combined treatments of the aforementioned agents on cell viability were investigated through the MTT experiment. Apoptotic effects were determined by Annexin V/PI and real-time PCR methods. In addition, a cell cycle analysis was used to determine the distribution of cells in the cycle. Data from experiments for 48 h showed that Bru, alone or in combination with 5-FU, is capable of causing an increase in the percentage of apoptotic cells in HT-29 cells compared to those of Erio alone or in combination with 5-FU. A significant increase in the level of bax and caspase-3 apoptotic genes was also detected in combinations of IC50 concentrations of Bru and 5-FU. These findings suggest that unlike Erio, Bru alone or in combination with 5-FU may be useful for increasing the effects of 5-FU used in the treatment of CRC and to provide data on alternative treatment approaches.
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Affiliation(s)
- Buse Ardıl
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, 48000, Mugla, Turkey
| | - Mehlika Alper
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, 48000, Mugla, Turkey.
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17
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Zhao L, Zhao H, Zhao Y, Sui M, Liu J, Li P, Liu N, Zhang K. Role of Ginseng, Quercetin, and Tea in Enhancing Chemotherapeutic Efficacy of Colorectal Cancer. Front Med (Lausanne) 2022; 9:939424. [PMID: 35795631 PMCID: PMC9252166 DOI: 10.3389/fmed.2022.939424] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 05/24/2022] [Indexed: 12/15/2022] Open
Abstract
As the most common gastrointestinal malignancy, colorectal cancer (CRC) remains a leading cause of cancer death worldwide. Although multimodal chemotherapy has effectively improved the prognosis of patients with CRC in recent years, severe chemotherapy-associated side effects and chemoresistance still greatly impair efficacy and limit its clinical application. In response to these challenges, an increasing number of traditional Chinese medicines have been used as synergistic agents for CRC administration. In particular, ginseng, quercetin, and tea, three common dietary supplements, have been shown to possess the potent capacity of enhancing the sensitivity of various chemotherapy drugs and reducing their side effects. Ginseng, also named “the king of herbs”, contains a great variety of anti-cancer compounds, among which ginsenosides are the most abundant and major research objects of various anti-tumor studies. Quercetin is a flavonoid and has been detected in multiple common foods, which possesses a wide range of pharmacological properties, especially with stronger anti-cancer and anti-inflammatory effects. As one of the most consumed beverages, tea has become particularly prevalent in both West and East in recent years. Tea and its major extracts, such as catechins and various constituents, were capable of significantly improving life quality and exerting anti-cancer effects both in vivo and in vitro. In this review, we mainly focused on the adjunctive effects of the three herbs and their constituents on the chemotherapy process of CRC.
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Affiliation(s)
- Linxian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu Zhao
- Gastroenterology and Center of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun, China
| | - Yongqing Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Mingxiu Sui
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jinping Liu
- Research Center of Natural Drugs, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Pingya Li
- Research Center of Natural Drugs, School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Ning Liu
- Department of Central Laboratory, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Ning Liu
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
- Kai Zhang
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18
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Synergistic effects of natural compounds and conventional chemotherapeutic agents: recent insights for the development of cancer treatment strategies. Heliyon 2022; 8:e09519. [PMID: 35669542 PMCID: PMC9163513 DOI: 10.1016/j.heliyon.2022.e09519] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/06/2022] [Accepted: 05/17/2022] [Indexed: 01/02/2023] Open
Abstract
Cancer is one of the leading causes of death in the world. Chemotherapy is presented as an option for treatment of this disease, however, low specificity, high resistance rates, toxicity and hypersensitivity reactions, make it necessary to search for therapeutic alternatives that increase the selectivity of treatment, reduce the side effects and enhance its antitumor potential. Natural products are accessible, inexpensive and less toxic sources; in addition, they have multiple mechanisms of action that can potentiate the outcome of chemotherapeutics. In this review, we present evidence on the beneficial effect of the interaction of dietary phytochemicals with chemotherapeutical agents for cancer treatment. This effect is generated by different mechanisms of action such as, increased tumoricidal effect via sensitization of cancer cells, reversing chemoresistance through inhibition of several targets involved in the development of drug resistance and, decreasing chemotherapy-induced toxicity in non-tumoral cells by the promotion of repair mechanisms. Studies discussed in this review will provide a solid basis for the exploration of the potential use of natural products in combination with chemotherapeutical agents, to overcome some of the difficulties that arise in the management of cancer patients.
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19
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Rodrigues R, Duarte D, Vale N. Drug Repurposing in Cancer Therapy: Influence of Patient’s Genetic Background in Breast Cancer Treatment. Int J Mol Sci 2022; 23:ijms23084280. [PMID: 35457144 PMCID: PMC9028365 DOI: 10.3390/ijms23084280] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients’ characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients’ genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.
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Affiliation(s)
- Rafaela Rodrigues
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; (R.R.); (D.D.)
| | - Diana Duarte
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; (R.R.); (D.D.)
- Faculty of Pharmacy of University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal; (R.R.); (D.D.)
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Associate Laboratory RISE–Health Research Network, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Correspondence: ; Tel.: +351-220426537
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20
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A Comprehensive View on the Quercetin Impact on Colorectal Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061873. [PMID: 35335239 PMCID: PMC8953922 DOI: 10.3390/molecules27061873] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) represents the third type of cancer in incidence and second in mortality worldwide, with the newly diagnosed case number on the rise. Among the diagnosed patients, approximately 70% have no hereditary germ-line mutations or family history of pathology, thus being termed sporadic CRC. Diet and environmental factors are to date considered solely responsible for the development of sporadic CRC; therefore; attention should be directed towards the discovery of preventative actions to combat the CRC initiation, promotion, and progression. Quercetin is a polyphenolic flavonoid plant secondary metabolite with a well-characterized antioxidant activity. It has been extensively reported as an anti-carcinogenic agent in the scientific literature, and the modulated targets of quercetin have been also characterized in the context of CRC, mainly in original research publications. In this fairly comprehensive review, we summarize the molecular targets of quercetin reported to date in in vivo and in vitro CRC models, while also giving background information about the signal transduction pathways that it up- and downregulates. Among the most relevant modulated pathways, the Wnt/β-catenin, PI3K/AKT, MAPK/Erk, JNK, or p38, p53, and NF-κB have been described. With this work, we hope to encourage further quests in the elucidation of quercetin anti-carcinogenic activity as single agent, as dietary component, or as pharmaconutrient delivered in the form of plant extracts.
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21
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Inhibition of Non-Small Cell Lung Cancer Proliferation and Survival by Rosemary Extract Is Associated with Activation of ERK and AMPK. Life (Basel) 2021; 12:life12010052. [PMID: 35054445 PMCID: PMC8779065 DOI: 10.3390/life12010052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/21/2021] [Accepted: 12/26/2021] [Indexed: 12/24/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) represents an aggressive form of lung cancer which often develops resistance to chemo- and radiotherapy emphasizing a need to identify novel treatment agents to combat it. Many plants contain compounds with anti-inflammatory, antimicrobial, antidiabetic, and anticancer properties and some plant-derived chemicals are used in the treatment of cancer. A limited number of in vitro and in vivo animal studies provide evidence of anticancer effects of rosemary (Rosmarinus officinalis) extract (RE); however, no studies have explored its role in H1299 NSCLC cells, and its underlying mechanism(s) of action are not understood. The current study examined the effects of RE on H1299 cell proliferation, survival, and migration using specific assays. Additionally, immunoblotting was used to investigate the effects of RE treatment on signalling molecules implicated in cell growth and survival. Treatment with RE dose-dependently inhibited H1299 proliferation with an IC50 value of 19 µg/mL. Similarly, RE dose-dependently reduced cell survival, and this reduction correlated with increased levels of cleaved poly (ADP-ribose) polymerase (PARP), a marker of apoptosis. RE was also able to inhibit cell migration as assessed with a wound healing assay. These cellular effects of RE were associated with an increase in phosphorylated levels of extracellular signal-regulated kinase (ERK), AMP-activated protein kinase (AMPK), and its downstream targets ACC, the mTORC1 protein raptor, and decreased p70S6K phosphorylation. More studies are required to fully examine the effects of RE against NSCLC.
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22
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Duarte D, Cardoso A, Vale N. Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs. Int J Mol Sci 2021; 22:ijms22147408. [PMID: 34299028 PMCID: PMC8306770 DOI: 10.3390/ijms22147408] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 02/06/2023] Open
Abstract
Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.
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Affiliation(s)
- Diana Duarte
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Armando Cardoso
- NeuroGen Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Correspondence:
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23
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Rana P, Shrama A, Mandal CC. Molecular insights into phytochemicals-driven break function in tumor microenvironment. J Food Biochem 2021; 45:e13824. [PMID: 34219240 DOI: 10.1111/jfbc.13824] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/06/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022]
Abstract
Advanced knowledge about the role of tumor microenvironment (TME) in cancer progression has opened various ways to target the vast signaling pathways for cancer treatment. Failures of the currently used drugs have raised out the need to look for novel drugs which can target various crucial aspects of cancer progression (e.g., angiogenesis, uncontrolled cell division, and metastasis). Phytochemicals behaving as potent anticancer agents shows promise as therapeutics. Various phytochemicals, such as curcumin, Epigallocatechin Gallate (EGCG), resveratrol, plumbagin, genistein, and others, have been identified with modulatory effect on TME. These phytochemicals often target the molecular pathways that reside in the tumor vicinity associated with endothelial cells, cancer-associated fibroblasts, immune cells, mesenchymal stem cells, other cell types, vascular and lymphatic networks, and extracellular matrix which are important for tumor progression and development. Some phytochemicals also target the internal signaling pathways, including STAT3, NF-қB, ERK-1/2, and PI3K/Akt signaling of noncancer cell, residing in the microenvironment, and thus inhibiting the supportive effect from these cells in tumor development. However, much information needs to be acquired before using these phytochemicals in cancer treatment. The primary objective of this review is to provide a better knowledge about the role of TME in cancer progression and development, focusing on the different targets which can be used for therapeutic approach, and then to give a brief account on some known phytochemicals to date, which have shown remarkable TME modulatory effects. PRACTICAL APPLICATIONS: For the use of phytochemicals as therapeutics, it is highly recommended that their precise target should be known; therefore studies should be encouraged such that the effects of these phytochemicals can be evaluated on the individual cellular level like how the phytochemical is targeting the tumor-associated macrophage, or any other cell residing in the tumor microenvironment (TME), and the compound should target a specific component of TME to avoid off target effects.
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Affiliation(s)
- Priyanshi Rana
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Amarjeet Shrama
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
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24
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Khan A, Siddiqui S, Husain SA, Mazurek S, Iqbal MA. Phytocompounds Targeting Metabolic Reprogramming in Cancer: An Assessment of Role, Mechanisms, Pathways, and Therapeutic Relevance. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:6897-6928. [PMID: 34133161 DOI: 10.1021/acs.jafc.1c01173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The metabolism of cancer is remarkably different from that of normal cells and confers a variety of benefits, including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefits. In the continued search for safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and attempt to make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the pharmacological interactions of phytocompounds with major metabolic pathways and evaluate the role of phytocompounds in the regulation of growth signaling and transcriptional programs involved in the metabolic transformation of cancer. Lastly, we examine the potential of these compounds in the clinical management of cancer along with limitations and challenges.
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Affiliation(s)
- Asifa Khan
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Shumaila Siddiqui
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Syed Akhtar Husain
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
| | - Sybille Mazurek
- Institute of Veterinary-Physiology and Biochemistry, University of Giessen, Giessen 35392, Germany
| | - Mohammad Askandar Iqbal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi 110025, India
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25
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Milczarek M, Pogorzelska A, Wiktorska K. Synergistic Interaction between 5-FU and an Analog of Sulforaphane-2-Oxohexyl Isothiocyanate-In an In Vitro Colon Cancer Model. Molecules 2021; 26:molecules26103019. [PMID: 34069385 PMCID: PMC8158758 DOI: 10.3390/molecules26103019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/14/2021] [Accepted: 05/16/2021] [Indexed: 12/22/2022] Open
Abstract
Combination therapy is based on the beneficial effects of pharmacodynamic interaction (synergistic or additive) between combined drugs or substances. A considerable group of candidates for combined treatments are natural compounds (e.g., isothiocyanates) and their analogs, which are tested in combination with anticancer drugs. We tested the anticancer effect of the combined treatment of isothiocyanate 2-oxohexyl isothiocyanate and 5-fluorouracil in colon and prostate cancer cell lines. The type of interaction was described using the Chou-Talalay method. The cytostatic and cytotoxic activities of the most promising combined treatments were investigated. In conclusion, we showed that combined treatment with 5-fluorouracil and 2-oxohexyl isothiocyanate acted synergistically in colon cancer. This activity is dependent on the cytostatic properties of the tested compounds and leads to the intensification of their individual cytotoxic activity. The apoptotic process is considered to be the main mechanism of cytotoxicity in this combined treatment.
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26
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Azar MRMH, Aghazadeh H, Mohammed HN, Sara MRS, Hosseini A, Shomali N, Tamjidifar R, Tarzi S, Mansouri M, Sarand SP, Marofi F, Akbari M, Xu H, Shotorbani SS. miR-193a-5p as a promising therapeutic candidate in colorectal cancer by reducing 5-FU and Oxaliplatin chemoresistance by targeting CXCR4. Int Immunopharmacol 2021; 92:107355. [PMID: 33429333 DOI: 10.1016/j.intimp.2020.107355] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/26/2020] [Accepted: 12/26/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide. The role of microRNAs (miRNAs/miRs) as small (19-25 nucleotides in length) non-coding RNA molecules that modify gene expression has been shown in several types of cancer. 5-Fluorouracil (5-FU) and oxaliplatin (Ox) are two common chemotherapeutic agents used to treat cancer. The present study aimed to evaluate the expression levels of miR-193a-5p in CRC, and its effect on the C-X-C Motif Chemokine Receptor 4 (CXCR4) target gene alone and in combination with chemotherapeutic drugs, to determine its possible role in chemoresistance. CRC tissues and adjacent non-cancerous tissue were obtained from 67 patients who had undergone surgery to determine the expression levels of miR-193a-5p and CXCR4. Subsequently, qPCR and Western blotting were performed to determine the effect of miR-193a-5p and chemotherapy drugs on CXCR4. َAlso, MTT assay, and flow cytometry was performed to determine their role in cell viability and apoptosis. Besides, the relationship between miR-193a-5p and CXCR4 with patients' clinical features was investigated. The results of the present study showed that miR-193a-5p was significantly downregulated, whereas CXCR4 was significantly upregulated in tumor tissues obtained from patients with CRC compared with the adjacent non-tumor healthy controls. In addition, the upregulation of miR-193-5p reduced the expression levels of CXCR4, particularly in combination with 5-FU and OX. Besides, using rescue experiments, the present study showed that miR-193a-5p replacement was able to suppress CXCR4-induced CRC cell proliferation by directly targeting CXCR4. Furthermore, there was a significant association between miR-193a-5p and CXCR4 with certain clinicopathological characteristics, particularly with metastasis-related features. These results suggest that miR-193a-5p serves a tumor-suppressive function in CRC and can directly target CXCR4 and decrease its mRNA and protein expression levels. Additionally, miR-193a-5p in combination with 5-FU and Ox potentiated reducing CXR4 expression, which may reveal its contribution to tumor chemoresistance. In conclusion, miR-193-5p may be applicable as a prognostic and diagnostic marker, and also serve as a therapeutic factor by reducing CXCR4 in combination with chemotherapeutic drugs.
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Affiliation(s)
| | - Hamed Aghazadeh
- Pharmaceutical Engineering Department, Faculty of Chemical Engineering, University of Tehran, Tehran 1417414418, Iran
| | | | - Mehdi Rezai Seghin Sara
- Department of Biochemistry, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Arezoo Hosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Rozita Tamjidifar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Department of Biology Ahar Branch, Islamic Azad University, Ahar 5451116714, Iran
| | - Saeed Tarzi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Department of Biology Ahar Branch, Islamic Azad University, Ahar 5451116714, Iran
| | - Mahmoud Mansouri
- University of Tehran, Master of Sciences in Applied Chemistry, Tehran 1417414418, Iran
| | - Sahar Pashaei Sarand
- Amirkabir University of Technology (Polytechnic of Tehran), Master of Sciences in Applied Chemistry, Tehran 441315875, Iran
| | - Faroogh Marofi
- Department of Hematology, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Huaxi Xu
- Department of Immunology, Center of Clinical Medicine and Laboratory, Jiangsu University, Zhenjiang 212013, Jiangsu Province, China.
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran; Department of Immunology, Center of Clinical Medicine and Laboratory, Jiangsu University, Zhenjiang 212013, Jiangsu Province, China.
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Oruganti L, Meriga B. Plant Polyphenolic Compounds Potentiates Therapeutic Efficiency of Anticancer Chemotherapeutic Drugs: A Review. Endocr Metab Immune Disord Drug Targets 2021; 21:246-252. [PMID: 32767950 DOI: 10.2174/1871530320666200807115647] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 04/15/2020] [Accepted: 05/19/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Scientific research continues to develop more efficacious drugs to treat and cure cancer, the dreadful disease threatening the human race. Chemotherapy is an essential means in cancer therapy, however, plant drugs having pharmacological safety, can be used alone or as additions to current chemotherapeutic agents to enhance therapeutic efficacy and minimize chemotherapyinduced adverse effects. OBJECTIVE A combination therapy where the synergistic effect on multiple targets is possible has gained significance because a one-drug one-target approach fails to yield the desired therapeutic effect. Therefore, a detailed description of important plant polyphenolic compounds with anticancer activity and their role in potentiating chemotherapeutic efficiency of existing anticancer drugs is provided in this review. Systematically screening combinations of active pharmaceutical ingredients for potential synergy with plant compounds may be especially valuable in cancer therapy. METHODS We extensively have gone through reviews and research articles available in the literature. We made use of databases such as Google Scholar, Research Gate, PubMed, Science Direct, etc. The following keywords were used in our literature search: "Chemotherapy, drug development, cancer drugs, plant-derived polyphenolics, synergistic studies, combination therapy, diagnosis and genetics." CONCLUSION Systematic research studies on screening combinations of plant phytochemicals with potential chemotherapeutic pharmaceuticals shed light on their synergistic effects, mechanisms of actions paving the way to develop more efficient anticancer therapeutics to treat and cure the cancer menace, to nullify chemotherapy-induced adverse effects and our review substantially contributes in this direction.
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Affiliation(s)
- Lokanatha Oruganti
- Department of Biochemistry, Cell Culture & Molecular Biology Lab, Sri Venkateswara University, Tirupati, India
| | - Balaji Meriga
- Department of Biochemistry, Cell Culture & Molecular Biology Lab, Sri Venkateswara University, Tirupati, India
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Song YY, Yuan Y, Shi X, Che YY. Improved drug delivery and anti-tumor efficacy of combinatorial liposomal formulation of genistein and plumbagin by targeting Glut1 and Akt3 proteins in mice bearing prostate tumor. Colloids Surf B Biointerfaces 2020; 190:110966. [PMID: 32199263 DOI: 10.1016/j.colsurfb.2020.110966] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/06/2020] [Accepted: 03/09/2020] [Indexed: 01/03/2023]
Abstract
Despite the plethora of significant research progress made to develop novel strategies for the treatment of prostate cancer, this disease remains one of the major global health challenges among men. However, using a co-treatment approach utilizing two or more anticancer drugs has shown tremendous success in the treatment of many cancer types. Nanoliposomes are well known to encapsulate multiple drugs and deliver them at the desired site. In this work, we report the synthesis of nanoliposomes (∼100 nm) encapsulating two drugs, plumbagin, and genistein, to synergistically inhibit the growth of prostate cancer cells. The combination of plumbagin and genistein drugs was found inhibiting xenograft prostate tumor growth by ∼80 % without any appreciable toxicity. Mechanistically, the combination of plumbagin and genistein containing nanoliposomes leads to the inhibition of PI3K/AKT3 signaling pathway as well as the decreased population of Glut-1 transporters to impart the retardation in tumor growth. Decrease in proliferative cells and blood vessels are early biological processes that laid the foundation of the observed anti-tumor effect. Thus, a novel, and non-toxic liposomal formulation, containing plumbagin and genistein drugs, is reported, which can deliver anticancer agents to prostate tumors and inhibit the growth.
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Affiliation(s)
- Yuan-Yuan Song
- Clinical Laboratory, The First Hospital of Jilin University, Changchun, 130021, China
| | - Ye Yuan
- Clinical Laboratory, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xu Shi
- Clinical Laboratory, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yuan-Yuan Che
- Clinical Laboratory, The First Hospital of Jilin University, Changchun, 130021, China.
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29
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Mazrouei R, Raeisi E, Lemoigne Y, Heidarian E. Activation of p53 Gene Expression and Synergistic Antiproliferative Effects of 5-Fluorouracil and β-escin on MCF7 Cells. JOURNAL OF MEDICAL SIGNALS & SENSORS 2019; 9:196-203. [PMID: 31544060 PMCID: PMC6743244 DOI: 10.4103/jmss.jmss_44_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
One of the most common malignancies in women is breast cancer. β-escin has pharmacological anticancer effects. 5-fluorouracil (5-FU) has antimetabolite and antiproliferative properties. The purpose of this study was to investigate the combined effects of 5-FU and β-escin on apoptosis, colony formation, Bcl-2 signaling protein, and p53 gene expression in MCF7 breast cancer cell line. The cytotoxic effects, the number of colonies, apoptosis, p53 gene expression, and Bcl-2 signaling protein of the combined 5-FU and β-escin on MCF7 cells were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, clonogenic assay, flow cytometry, real-time quantitative polymerase chain reaction, and western blotting methods, respectively. Half-maximal inhibitory concentration values of β-escin and 5-FU were 80 μg/ml and 2 μM, respectively. The combination of 5-FU and β-escin on MCF7 cell viability showed a combination index equal to 0.5. The expression of p53 and apoptosis increased in the combination of 5-FU and β-escin on MCF7 cells compared to that of control group (P < 0.05). In addition, the number of colonies and Bcl-2 signaling protein in combination of 5-FU and β-escin decreased with respect to untreated control cells or single treatment of 5-FU and β-escin. The combination of 5-FU and β-escin not only has synergistic effects by increasing cell apoptosis and p53 gene expression but also decreases Bcl-2 signaling protein in MCF7 cell lines.
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Affiliation(s)
- Raziyeh Mazrouei
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Raeisi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Medical Physics and Radiology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Esfandiar Heidarian
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Pintova S, Dharmupari S, Moshier E, Zubizarreta N, Ang C, Holcombe RF. Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol 2019; 84:591-598. [PMID: 31203390 DOI: 10.1007/s00280-019-03886-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 06/04/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND Epidemiologic and preclinical data suggest isoflavones have anticancer activity in colorectal malignancy prevention and treatment. This is the first clinical trial assessing safety and tolerability of Genistein in combination with chemotherapy in metastatic colorectal cancer. METHODS Patients who had histologically confirmed metastatic colorectal cancer and had not received previous treatment were eligible to enroll. Subjects were treated with FOLFOX or FOLFOX-Bevacizumab as per the investigator choice. Genistein was administered orally for 7 days every 2 weeks, beginning 4 days prior to chemotherapy and continuing through days 1-3 of infusional chemotherapy. Primary endpoint was safety and secondary endpoints included cycle 6 response rate, best overall response rate (BOR), and median progression-free survival (PFS). RESULTS Thirteen patients received chemotherapy with Genistein in this trial. The most common adverse events related to Genistein alone were mild and included headaches, nausea, and hot flashes. One subject was observed to have grade 3 hypertension. No increase in chemotherapy-related adverse events was observed when Genistein was added. BOR and median PFS were 61.5% and 11.5 months, respectively. CONCLUSION We observed that adding Genistein to FOLFOX or FOLFOX-Bevacizumab was safe and tolerable. Efficacy results are notable and warrant verification in larger clinical trials. CLINICAL TRIAL REGISTRATION The study was registered at ClinicalTrials.gov Identifier: NCT01985763.
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Affiliation(s)
- Sofya Pintova
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA. .,Mount Sinai Hospital, One Gustave L Levy Place, Box 1128, New York, NY, 10029, USA.
| | - Sirish Dharmupari
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA
| | - Erin Moshier
- Department of Population Health Science and Policy, Institute for Healthcare Delivery Science, Icahn School of Medicine At Mount Sinai, New York, NY, USA
| | - Nicole Zubizarreta
- Department of Population Health Science and Policy, Institute for Healthcare Delivery Science, Icahn School of Medicine At Mount Sinai, New York, NY, USA
| | - Celina Ang
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA
| | - Randall F Holcombe
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine At Mount Sinai, New York, NY, USA.,University of Hawai'I Cancer Center, Honolulu, HI, USA
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Ye Q, Liu K, Shen Q, Li Q, Hao J, Han F, Jiang RW. Reversal of Multidrug Resistance in Cancer by Multi-Functional Flavonoids. Front Oncol 2019; 9:487. [PMID: 31245292 PMCID: PMC6581719 DOI: 10.3389/fonc.2019.00487] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 05/23/2019] [Indexed: 12/22/2022] Open
Abstract
Multidrug resistance (MDR) resulting from different defensive mechanisms in cancer is one of the major obstacles of clinical treatment. To circumvent MDR many reversal agents have been developed, but most of them fail in clinical trials due to severely adverse effects. Recently, certain natural products have been reported to overcome MDR, including flavonoids which are abundant in plants, foods, and herbs. The structure of flavonoids can be abbreviated as C6-C3-C6 (C for carbon), and further categorized into flavonoids, iso-flavonoids and neo-flavonoids, according to their structural backbones. Flavonoids possess multiple bioactivities, and a growing body of research has indicated that both flavonoids and iso-flavonoids can either kill or re-sensitize conventional chemotherapeutics to resistant cancer cells. Here, we summarize the research and discuss the underlying mechanisms, concluding that these flavonoids do not function as specific regulators of target proteins, but rather as multi-functional agents that negatively regulate the key factors contributing to MDR.
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Affiliation(s)
| | - Kai Liu
- Hainan General Hospital, Haikou, China
| | - Qun Shen
- Hainan General Hospital, Haikou, China
| | | | - Jinghui Hao
- Jiaozuo Second People's Hospital, Jiaozuo, China
| | | | - Ren-Wang Jiang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou, China
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Sen K, Banerjee S, Mandal M. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf B Biointerfaces 2019; 180:9-22. [PMID: 31015105 DOI: 10.1016/j.colsurfb.2019.04.035] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/26/2019] [Accepted: 04/15/2019] [Indexed: 01/06/2023]
Abstract
Multidrug-based combinatorial therapeutic regiments which target multiple pathways simultaneously are being utilized as a therapeutic strategy of choice due to reduction in toxicity profile and enhancement of therapeutic index of the individual drugs. 5-Fluorouracil is a clinically approved drug which has limited response rate in the realm of colorectal cancer amelioration, hence our study aims to improve its efficacy by aiming the simultaneous delivery of 5-Flurouracil and apigenin which is naturally occurring flavone abundantly present in fruit and vegetables through a single liposome to combat and control colorectal cancer effectively in-vitro and in-vivo. The liposomal nanocarrier bearing the anti-tumorigenic agent apigenin was designed in this study in order to improve the bioavailability of the flavone while at the same time achieve combinatorial drug regime with 5- Fluorouracil. This study reports the synthesis and production of a relatively robust dual drug-loaded liposomal formulation by modified thin film hydration method which substantially entraps both the drugs. Even though there have been reports of the combinatorial regimen involving apigenin and 5-Flurouracil our study reports the optimal molar ratio for effective synergistic therapeutic application of this drug combination to alleviate colorectal cancer. The cytotoxicity and cellular effects of individual, combinatorial free drugs and their liposomal counterparts tested against two human colon cancer cell lines revealed significantly higher cytotoxicity of the dual-drug liposomes. The dual-drug liposomes demonstrated enhanced inhibition of angiogenesis, better reduction in cell proliferation and increased apoptotic potential. Cell signaling studies indicating a significant upregulation of pAMPK and activity against downstream targets by dual drug liposomes suggested its role in the reversal of Warburg effect. The formulation was tested in a preclinical setting in nude mice tumor xenograft model and was found to have greater anti-neoplastic and anti-tumorigenic effect. The study indicated that the increased chemotherapeutic potential in vivo was due to the passive targeting achieved by the liposomal drug loaded nano-carrier and the synergistic effect of apigenin in 5-Fluorouracil treatment offers a new attractive alternative to enhance the therapeutic potency of drugs and paves way for potential clinical applications.
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Affiliation(s)
- Kacoli Sen
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India
| | - Shubhadeep Banerjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India.
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Nanoliposomal formulation encapsulating celecoxib and genistein inhibiting COX-2 pathway and Glut-1 receptors to prevent prostate cancer cell proliferation. Cancer Lett 2019; 448:1-10. [DOI: 10.1016/j.canlet.2019.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/18/2018] [Accepted: 01/08/2019] [Indexed: 12/21/2022]
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Serum Concentration of Genistein, Luteolin and Colorectal Cancer Prognosis. Nutrients 2019; 11:nu11030600. [PMID: 30871032 PMCID: PMC6472030 DOI: 10.3390/nu11030600] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 03/01/2019] [Accepted: 03/05/2019] [Indexed: 12/31/2022] Open
Abstract
Although flavonoid phytoestrogens have been suggested to be associated with reduced risk of colorectal cancer (CRC), their influence on CRC prognosis remains uncertain. A population-based cohort of 2051 patients diagnosed with stage I⁻III CRC in southwest Germany in 2003⁻2010 were followed for five years. Post-diagnostic serum concentration of genistein and luteolin were measured using Ultra-Performance Liquid Chromatography with mass spectrometry. Multivariable Cox regression analysis was conducted to calculate the Hazard Ratios (HRs) and 95% confidence interval (CI) for the association between flavonoids concentration and overall morality, CRC-specific mortality, CRC recurrence, and disease-free survival (DFS). Median (interquartile range) serum concentration of genistein and luteolin was 11.90 ng/µL (10.08⁻14.13) and 7.20 ng/µL (6.40⁻8.16), respectively. Neither serum genistein nor luteolin was associated with CRC prognosis. There was no clear evidence of departure from linearity. However, the association might be differential by adjuvant chemotherapy. Associations pointed towards lower risk in patients who received chemotherapy and higher risk in those without chemotherapy for overall mortality regarding serum genistein (P-interaction = 0.02) and correspondingly for CRC recurrence (P-interaction: 0.03) and DFS (P-interaction: 0.01) with respect to luteolin. Our study provides little evidence that serum genistein and luteolin are associated with colorectal cancer prognosis. Future studies are warranted to evaluate the potential interaction with adjuvant chemotherapy.
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35
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Cheng X, Xu X, Chen D, Zhao F, Wang W. Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer. Biomed Pharmacother 2019; 110:473-481. [PMID: 30530050 DOI: 10.1016/j.biopha.2018.11.082] [Citation(s) in RCA: 313] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 11/05/2018] [Accepted: 11/19/2018] [Indexed: 12/24/2022] Open
Abstract
Aberrant Wnt/β-catenin signaling has often been reported in different cancers, particularly colorectal cancer (CRC), and this signaling cascade is central to carcinogenesis. Approximately 80% of CRC cases harbor mutations in the adenomatous polyposis coli gene, and half of the remaining cases feature mutations in the β-catenin gene that affect the Wnt/β-catenin signaling pathway. Unsurprisingly, the Wnt/β-catenin signaling pathway has potential value as a therapeutic target in the treatment of CRC. Several inhibitors of the Wnt/β-catenin signaling pathway have been developed for CRC treatment, but so far no molecular therapeutic targeting this pathway has been incorporated into oncological practice. In this review, we discuss the role of Wnt/β-catenin signaling in CRC and its potential as a target of innovative therapeutic approaches for CRC.
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Affiliation(s)
- Xiaofei Cheng
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangming Xu
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Dong Chen
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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36
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Costea T, Hudiță A, Ciolac OA, Gălățeanu B, Ginghină O, Costache M, Ganea C, Mocanu MM. Chemoprevention of Colorectal Cancer by Dietary Compounds. Int J Mol Sci 2018; 19:E3787. [PMID: 30487390 PMCID: PMC6321468 DOI: 10.3390/ijms19123787] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/18/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the leading causes of death, and the third most diagnosed type of cancer, worldwide. It is most common amongst men and women over 50 years old. Risk factors include smoking, alcohol, diet, physical inactivity, genetics, alterations in gut microbiota, and associated pathologies (diabetes, obesity, chronic inflammatory bowel diseases). This review will discuss, in detail, the chemopreventive properties of some dietary compounds (phenolic compounds, carotenoids, iridoids, nitrogen compounds, organosulfur compounds, phytosterols, essential oil compounds, polyunsaturated fatty acids and dietary fiber) against colorectal cancer. We present recent data, focusing on in vitro, laboratory animals and clinical trials with the previously mentioned compounds. The chemopreventive properties of the dietary compounds involve multiple molecular and biochemical mechanisms of action, such as inhibition of cell growth, inhibition of tumor initiation, inhibition of adhesion, migration and angiogenesis, apoptosis, interaction with gut microbiota, regulation of cellular signal transduction pathways and xenobiotic metabolizing enzymes, etc. Moreover, this review will also focus on the natural dietary compounds' bioavailability, their synergistic protective effect, as well as the association with conventional therapy. Dietary natural compounds play a major role in colorectal chemoprevention and continuous research in this field is needed.
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Affiliation(s)
- Teodora Costea
- Department of Pharmacognosy, Phytochemistry and Phytotherapy, "Carol Davila" University of Medicine and Pharmacy, 020956 Bucharest, Romania.
| | - Ariana Hudiță
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Oana-Alina Ciolac
- Department of Biophysics, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
| | - Bianca Gălățeanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Octav Ginghină
- Department of Surgery, "Sf. Ioan" Emergency Clinical Hospital, 042122 Bucharest, Romania.
- Department II, Faculty of Dental Medicine, "Carol Davila" University of Medicine and Pharmacy, 030167 Bucharest, Romania.
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania.
| | - Constanța Ganea
- Department of Biophysics, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
| | - Maria-Magdalena Mocanu
- Department of Biophysics, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
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Guerra AR, Duarte MF, Duarte IF. Targeting Tumor Metabolism with Plant-Derived Natural Products: Emerging Trends in Cancer Therapy. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:10663-10685. [PMID: 30227704 DOI: 10.1021/acs.jafc.8b04104] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Recognition of neoplastic metabolic reprogramming as one of cancer's hallmarks has paved the way for developing novel metabolism-targeted therapeutic approaches. The use of plant-derived natural bioactive compounds for this endeavor is especially promising, due to their diverse structures and multiple targets. Hence, over the past decade, a growing number of studies have assessed the impact of phytochemicals on tumor cell metabolism, aiming at improving current knowledge on their mechanisms of action and, at the same time, evaluating their potential as anti-cancer metabolic modulators. In this Review, we focus on three classes of plant-derived compounds with promising anti-cancer activity-phenolic compounds, isoprenoids, and alkaloids-to describe their effects on major energetic and biosynthetic pathways of human tumor cells. Such a comprehensive and integrated account of the ability of these compounds to hit different metabolic targets is expected to contribute to the rational design and critical assessment of novel anti-cancer therapies based on natural-product-mediated metabolic reprogramming.
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Affiliation(s)
- Angela R Guerra
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
| | - Maria F Duarte
- Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja , Apartado 6158 , 7801-908 Beja , Portugal
- ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas , Universidade de Évora , Pólo da Mitra, 7006-554 Évora , Portugal
| | - Iola F Duarte
- CICECO - Instituto de Materiais de Aveiro, Departamento de Quı́mica , Universidade de Aveiro , Campus de Santiago , 3810-193 Aveiro , Portugal
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Abstract
Despite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents.
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Affiliation(s)
- Christine M Veenstra
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - John C Krauss
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Desai SJ, Prickril B, Rasooly A. Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer. Nutr Cancer 2018; 70:350-375. [PMID: 29578814 DOI: 10.1080/01635581.2018.1446091] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways. Cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism, is upregulated during both inflammation and cancer. COX-2 is induced by pro-inflammatory cytokines at the site of inflammation and enhanced COX-2-induced synthesis of prostaglandins stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases metastatic potential. As a result, COX-2 inhibitors are a subject of intense research interest toward potential clinical applications. Epidemiological studies highlight the potential benefits of diets rich in phytonutrients for cancer prevention. Plants contain numerous phytonutrient secondary metabolites shown to modulate COX-2. Studies have shown that these metabolites, some of which are used in traditional medicine, can reduce inflammation and carcinogenesis. This review describes the molecular mechanisms by which phytonutrients modulate inflammation, including studies of carotenoids, phenolic compounds, and fatty acids targeting various inflammation-related molecules and pathways associated with cancer. Examples of pathways include those of COX-2, mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase, pro-inflammatory cytokines, and transcription factors like nuclear factor kappa B. Such phytonutrient modulation of COX-2 and inflammation continue to be explored for applications in the prevention and treatment of cancer.
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Affiliation(s)
- Shreena J Desai
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
| | - Ben Prickril
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
| | - Avraham Rasooly
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
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40
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Shin EJ, Choi HK, Sung MJ, Park JH, Chung MY, Chung S, Hwang JT. Anti-tumour effects of beta-sitosterol are mediated by AMPK/PTEN/HSP90 axis in AGS human gastric adenocarcinoma cells and xenograft mouse models. Biochem Pharmacol 2018; 152:60-70. [PMID: 29559312 DOI: 10.1016/j.bcp.2018.03.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 03/09/2018] [Indexed: 01/08/2023]
Abstract
We investigated the anti-cancer effects of beta-sitosterol (BS), a plant-derived sterol in AGS human gastric adenocarcinoma cells and xenograft mouse models. BS significantly reduced cell viability by inducing apoptosis in AGS adenocarcinoma cells. This was accompanied by the formation of apoptotic bodies, as detected by Annexin V, caspase 3/7 activity, and MitoPotential assay. BS stimulated phosphatase and tensin homolog (PTEN) and phospho-AMP-activated protein kinase (p-AMPK) expression. Pharmacological inhibitors or siRNA were used to further analyse the relationship between the two proteins. AMPK was found to represent a likely upstream regulator of PTEN. Additionally, two-dimensional gel electrophoresis was used to identify related proteins in the treatment of BS. The decrease of Hsp90 protein by BS was observed. Induction of PTEN protein and reduction of Hsp90 was mediated by AICAR, an AMPK activator, indicating that AMPK is necessary for PTEN and Hsp90 expression. Additionally, BS was found to be effective through the regulation of cancer biomarker. Furthermore, BS suppressed tumour growth without toxicity in the AGS xenograft mouse models-. Taken together, the present results demonstrate that BS exerts anti-cancer effects in AGS cells and xenograft mouse models by mediating AMPK, PTEN, and Hsp90.
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Affiliation(s)
- Eun Ju Shin
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea; Department of Food Biotechnology, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Hyo-Kyoung Choi
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea
| | - Mi Jeong Sung
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea
| | - Jae Ho Park
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea
| | - Min-Yu Chung
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea
| | - Sangwon Chung
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea
| | - Jin-Taek Hwang
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea; Department of Food Biotechnology, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
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Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4154185. [PMID: 29568751 PMCID: PMC5820674 DOI: 10.1155/2018/4154185] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/08/2017] [Accepted: 12/17/2017] [Indexed: 02/08/2023]
Abstract
Polyphenols have been reported to have wide spectrum of biological activities including major impact on initiation, promotion, and progression of cancer by modulating different signalling pathways. Colorectal cancer is the second most major cause of mortality and morbidity among females and the third among males. The objective of this review is to describe the activity of a variety of polyphenols in colorectal cancer in clinical trials, preclinical studies, and primary research. The molecular mechanisms of major polyphenols related to their beneficial effects on colorectal cancer are also addressed. Synthetic modifications and other future directions towards exploiting of natural polyphenols against colorectal cancer are discussed in the last section.
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Bansal M, Singh N, Pal S, Dev I, Ansari KM. Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer. ADVANCES IN MOLECULAR TOXICOLOGY 2018. [DOI: 10.1016/b978-0-444-64199-1.00004-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Natural compounds and combination therapy in colorectal cancer treatment. Eur J Med Chem 2018; 144:582-594. [DOI: 10.1016/j.ejmech.2017.12.039] [Citation(s) in RCA: 251] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 12/17/2022]
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Boueroy P, Hahnvajanawong C, Boonmars T, Saensa-ard S, Wattanawongdon W, Kongsanthia C, Salao K, Wongwajana S, Anantachoke N, Reutrakul V. Synergistic Effect of Forbesione From Garcinia hanburyi in Combination with 5-Fluorouracil on Cholangiocarcinoma. Asian Pac J Cancer Prev 2017; 18:3343-3351. [PMID: 29286229 PMCID: PMC5980893 DOI: 10.22034/apjcp.2017.18.12.3343] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background: Chemotherapy for advanced cholangiocarcinoma (CCA) is largely ineffective; thus innovative combinations of chemotherapeutic agents and natural compounds represent a promising strategy. This study aimed to investigate the synergistic effects of forbesione combined with 5-fluorouracil (5-FU) in hamster cholangiocarcinoma (Ham-1) cells both in vitro and in vivo. The anti-tumor effects of 5-FU combined with forbesione in vitro were determined using the Sulforhodamine B (SRB) assay and the effects in vivo were assessed in transplanted Ham-1 allograph models. Using ethidium bromide/acridine orange (EB/AO) staining, the morphological changes of apoptotic cells was investigated. The expressions of apoptosis-related molecules after combined treatment with forbesione and 5-FU were determined using real-time RT-PCR and western blot analysis. Forbesione or 5-FU alone inhibited proliferation of Ham-1 cells in a dose-dependent manner and their combination showed a synergistic proliferation inhibitory effect in vitro. In vivo studies, forbesione in combination with 5-FU exhibited greater inhibition of the tumor in the hamster model compared with treatment using either drug alone. Forbesione combined with 5-FU exerted stronger apoptotic induction in Ham-1 cells than did single drug treatment. The combination of drugs strongly suppressed the expression of B-cell lymphoma 2 (Bcl-2) and procaspase-3 while enhancing the expression of p53, Bcl-2-associated X protein (Bax), apoptotic protease activating factor-1 (Apaf-1), caspase-9 and caspase-3, compared with single drug treatments. These results explained the decreased expression of cytokeratin 19 (CK19) positive cells and proliferation cell nuclear antigen (PCNA) positive cells in Ham-1 cell tumor tissues of the treated hamsters. There was no apparent systemic toxicity observed in the treated animals compared with the control groups. Forbesione combined with 5-FU strongly induced apoptosis in Ham-1 cells. The growth inhibitory effect of combined treatment using these two drugs was much greater than treatment with either drug alone, both in vitro and in vivo.
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Affiliation(s)
- Parichart Boueroy
- Department of Microbiology, Khon Kaen University, Khon Kaen 40002, Thailand
- Liver Fluke and Cholangiocarcinoma Research Center, Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen 40002, Thailand
- Center of Excellence for Innovation in Chemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
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Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis. Anticancer Drugs 2017; 28:831-840. [PMID: 28816773 DOI: 10.1097/cad.0000000000000517] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells.
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46
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Sun X, Zhu MJ. AMP-activated protein kinase: a therapeutic target in intestinal diseases. Open Biol 2017; 7:170104. [PMID: 28835570 PMCID: PMC5577448 DOI: 10.1098/rsob.170104] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 07/25/2017] [Indexed: 02/07/2023] Open
Abstract
Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a highly conserved energy sensor, has a crucial role in cardiovascular, neurodegenerative and inflammatory diseases, as well as in cancer and metabolic disorders. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. AMPK inactivation is an aetiological factor in intestinal dysfunctions. This review summarizes the favourable outcomes of AMPK activation on intestinal health, and discusses AMPK as a potential therapeutic target for intestinal diseases.
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Affiliation(s)
- Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA
- School of Food Science, University of Idaho, Moscow, ID 83844, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA
- School of Food Science, University of Idaho, Moscow, ID 83844, USA
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Mouhid L, Corzo-Martínez M, Torres C, Vázquez L, Reglero G, Fornari T, Ramírez de Molina A. Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems. JOURNAL OF ONCOLOGY 2017; 2017:7351976. [PMID: 28555156 PMCID: PMC5438845 DOI: 10.1155/2017/7351976] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/06/2017] [Indexed: 02/07/2023]
Abstract
Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.
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Affiliation(s)
- Lamia Mouhid
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
| | - Marta Corzo-Martínez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Carlos Torres
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Luis Vázquez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Guillermo Reglero
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Tiziana Fornari
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
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48
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Redondo-Blanco S, Fernández J, Gutiérrez-Del-Río I, Villar CJ, Lombó F. New Insights toward Colorectal Cancer Chemotherapy Using Natural Bioactive Compounds. Front Pharmacol 2017; 8:109. [PMID: 28352231 PMCID: PMC5348533 DOI: 10.3389/fphar.2017.00109] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/22/2017] [Indexed: 12/12/2022] Open
Abstract
Combination therapy consists in the simultaneous administration of a conventional chemotherapy drug (or sometimes, a radiotherapy protocol) together with one or more natural bioactives (usually from plant or fungal origin) of small molecular weight. This combination of anticancer drugs may be applied to cell cultures of tumor cells, or to an animal model for a cancer type (or its xenograft), or to a clinical trial in patients. In this review, we summarize current knowledge describing diverse synergistic effects on colorectal cancer cell cultures, animal models, and clinical trials of various natural bioactives (stilbenes, flavonoids, terpenes, curcumin, and other structural families), which may be important with respect to diminish final doses of the chemotherapy drug, although maintaining its biological effect. This is important as these approaches may help reduce side effects in patients under conventional chemotherapy. Also, these molecules may exerts their synergistic effects via different cell cycle pathways, including different ones to those responsible of resistance phenotypes: transcription factors, membrane receptors, adhesion and structural molecules, cell cycle regulatory components, and apoptosis pathways.
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Affiliation(s)
- Saúl Redondo-Blanco
- Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Oviedo, Spain
| | - Javier Fernández
- Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Oviedo, Spain
| | - Ignacio Gutiérrez-Del-Río
- Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Oviedo, Spain
| | - Claudio J Villar
- Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Oviedo, Spain
| | - Felipe Lombó
- Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo Oviedo, Spain
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49
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Ullah MF, Bhat SH, Husain E, Abu-Duhier F, Hadi SM, Sarkar FH, Ahmad A. Pharmacological Intervention through Dietary Nutraceuticals in Gastrointestinal Neoplasia. Crit Rev Food Sci Nutr 2017; 56:1501-18. [PMID: 25365584 DOI: 10.1080/10408398.2013.772091] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neoplastic conditions associated with gastrointestinal (GI) tract are common worldwide with colorectal cancer alone accounting for the third leading rate of cancer incidence. Other GI malignancies such as esophageal carcinoma have shown an increasing trend in the last few years. The poor survival statistics of these fatal cancer diseases highlight the need for multiple alternative treatment options along with effective prophylactic strategies. Worldwide geographical variation in cancer incidence indicates a correlation between dietary habits and cancer risk. Epidemiological studies have suggested that populations with high intake of certain dietary agents in their regular meals have lower cancer rates. Thus, an impressive embodiment of evidence supports the concept that dietary factors are key modulators of cancer including those of GI origin. Preclinical studies on animal models of carcinogenesis have reflected the pharmacological significance of certain dietary agents called as nutraceuticals in the chemoprevention of GI neoplasia. These include stilbenes (from red grapes and red wine), isoflavones (from soy), carotenoids (from tomatoes), curcuminoids (from spice turmeric), catechins (from green tea), and various other small plant metabolites (from fruits, vegetables, and cereals). Pleiotropic action mechanisms have been reported for these diet-derived chemopreventive agents to retard, block, or reverse carcinogenesis. This review presents a prophylactic approach to primary prevention of GI cancers by highlighting the translational potential of plant-derived nutraceuticals from epidemiological, laboratory, and clinical studies, for the better management of these cancers through consumption of nutraceutical rich diets and their intervention in cancer therapeutics.
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Affiliation(s)
- Mohammad F Ullah
- a Prince Fahad Research Chair , Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk , Tabuk , Saudi Arabia
| | - Showket H Bhat
- a Prince Fahad Research Chair , Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk , Tabuk , Saudi Arabia
| | - Eram Husain
- a Prince Fahad Research Chair , Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk , Tabuk , Saudi Arabia
| | - Faisel Abu-Duhier
- a Prince Fahad Research Chair , Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk , Tabuk , Saudi Arabia
| | - S M Hadi
- b Department of Biochemistry , Faculty of Life Sciences, Aligarh Muslim University , Uttar Pradesh , India
| | - Fazlul H Sarkar
- c Department of Pathology , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , Michigan USA
| | - Aamir Ahmad
- c Department of Pathology , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , Michigan USA
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50
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Marín-Aguilar F, Pavillard LE, Giampieri F, Bullón P, Cordero MD. Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds. Int J Mol Sci 2017; 18:E288. [PMID: 28146060 PMCID: PMC5343824 DOI: 10.3390/ijms18020288] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 01/18/2017] [Accepted: 01/23/2017] [Indexed: 01/15/2023] Open
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor which is activated by increases in adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and/or adenosine diphosphate (ADP)/ATP ratio, and increases different metabolic pathways such as fatty acid oxidation, glucose transport and mitochondrial biogenesis. In this sense, AMPK maintains cellular energy homeostasis by induction of catabolism and inhibition of ATP-consuming biosynthetic pathways to preserve ATP levels. Several studies indicate a reduction of AMPK sensitivity to cellular stress during aging and this could impair the downstream signaling and the maintenance of the cellular energy balance and the stress resistance. However, several diseases have been related with an AMPK dysfunction. Alterations in AMPK signaling decrease mitochondrial biogenesis, increase cellular stress and induce inflammation, which are typical events of the aging process and have been associated to several pathological processes. In this sense, in the last few years AMPK has been identified as a very interesting target and different nutraceutical compounds are being studied for an interesting potential effect on AMPK induction. In this review, we will evaluate the interaction of the different nutraceutical compounds to induce the AMPK phosphorylation and the applications in diseases such as cancer, type II diabetes, neurodegenerative diseases or cardiovascular diseases.
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Affiliation(s)
- Fabiola Marín-Aguilar
- Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain.
| | - Luis E Pavillard
- Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain.
| | - Francesca Giampieri
- Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica, Università Politecnica delle Marche, Ancona 60100, Italy.
| | - Pedro Bullón
- Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain.
| | - Mario D Cordero
- Research Laboratory, Oral Medicine Department, University of Sevilla, Sevilla 41009, Spain.
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