Login Register Cart 0
Generic placeholder image

Current Cancer Therapy Reviews

Editor-in-Chief

ISSN (Print): 1573-3947
ISSN (Online): 1875-6301

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

The Effect of Metformin on Bad, Bak, and Bim Pro-apoptotic Factors: A Molecular Dynamic Simulation Study

Author(s): Navid Jamali, Zohreh Mostafavi-Pour*, Javad Saffari-Chaleshtori and Mohammad Samare-Najaf

Volume 19, Issue 1, 2023

Published on: 23 December, 2022

Page: [74 - 81] Pages: 8

DOI: 10.2174/1573394718666220930143651

Price: $65

Abstract

Background: Recent investigations have demonstrated that metformin treatment can decrease tumor incidence and growth using cell cycle arrest and induction of apoptosis pathway. However, it is not clear how metformin affects the factors involved in the apoptotic process.

Objective: The present study aimed to determine the effect of metformin on Bak, Bad, and Bim proapoptotic proteins using docking and dynamics simulation studies.

Methods: The 3D structure of molecules was retrieved from PubChem and RCSB servers. Simulation and docking studies were conducted by Gromacs and AutoDock software. Next, molecular dynamics analysis was performed using Gromacs software. Moreover, LigPlot+V.4.5.3 software was applied for the determination of the hydrogen and hydrophobic interactions at the binding sites.

Results: Our findings demonstrated that metformin has the highest affinity for binding the Bak protein. This binding occurred using four amino acid residues within the binding site of Bak with the minimum binding energy (-5.70 kcal/mol). The molecular docking of metformin to these proapoptotic factors significantly decreased the total energy and increased the coil secondary structure of Bak protein.

Conclusion: According to our findings, metformin can alter the molecular dynamics property of these proteins, which results in increased activity of these pro-apoptotic proteins and induction of apoptosis.

Keywords: Tumor, metformin, apoptosis, molecular docking, protein conformation, three-dimensional structure.

« Previous
Graphical Abstract

[1]
Luengo A, Sullivan LB, Heiden MGV. Understanding the complexity of metformin action: Limiting mitochondrial respiration to improve cancer therapy. BMC Biol 2014; 12(1): 82.
[http://dx.doi.org/10.1186/s12915-014-0082-4] [PMID: 25347702]
[2]
Gupta G, de Jesus Andreoli Pinto T. Chellappan DK, Mishra A, Malipeddi H, Dua K. A clinical update on metformin and lung cancer in diabetic patients. Panminerva Med 2018; 60(2): 70-5.
[http://dx.doi.org/10.23736/S0031-0808.18.03394-3] [PMID: 29370676]
[3]
EL-Arabey AA. Update on off label use of metformin for obesity. Prim Care Diabetes 2018; 12(3): 284-5.
[http://dx.doi.org/10.1016/j.pcd.2018.02.004] [PMID: 29525383]
[4]
Dulskas A, Patasius A, Linkeviciute-Ulinskiene D, Zabuliene L, Smailyte G. A cohort study of antihyperglycemic medication exposure and survival in patients with gastric cancer. Aging 2019; 11(17): 7197-205.
[http://dx.doi.org/10.18632/aging.102245] [PMID: 31518336]
[5]
Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 2017; 60(9): 1639-47.
[http://dx.doi.org/10.1007/s00125-017-4372-6] [PMID: 28776080]
[6]
Thakur S, Daley B, Klubo-Gwiezdzinska J. The role of an anti-diabetic drug metformin in the treatment of endocrine tumors. J Mol Endocrinol 2019; 63(2): R17-35.
[http://dx.doi.org/10.1530/JME-19-0083] [PMID: 31307011]
[7]
Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009; 8(6): 909-15.
[http://dx.doi.org/10.4161/cc.8.6.7933] [PMID: 19221498]
[8]
Sahra IB, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008; 27(25): 3576-86.
[http://dx.doi.org/10.1038/sj.onc.1211024] [PMID: 18212742]
[9]
Emanuele S, Oddo E, D’Anneo A, et al. Routes to cell death in animal and plant kingdoms: From classic apoptosis to alternative ways to die-a review. Rend Lincei Sci Fis Nat 2018; 29(2): 397-409.
[http://dx.doi.org/10.1007/s12210-018-0704-9]
[10]
Corbalan JJ, Vatner DE, Vatner SF. Myocardial apoptosis in heart disease: Does the emperor have clothes? Basic Res Cardiol 2016; 111(3): 31.
[http://dx.doi.org/10.1007/s00395-016-0549-2] [PMID: 27043720]
[11]
Cui Y, Lu P, Song G, Liu Q, Zhu D, Liu X. Involvement of PI3K/Akt, ERK and p38 signaling pathways in emodin-mediated extrinsic and intrinsic human hepatoblastoma cell apoptosis. Food Chem Toxicol 2016; 92: 26-37.
[http://dx.doi.org/10.1016/j.fct.2016.03.013] [PMID: 27032576]
[12]
Kim HJ, Seo BG, Kim KD, et al. C5, A Cassaine diterpenoid amine, induces apoptosis via the extrinsic pathways in human lung cancer cells and human lymphoma cells. Int J Mol Sci 2020; 21(4): 1298.
[http://dx.doi.org/10.3390/ijms21041298] [PMID: 32075108]
[13]
Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407(6805): 770-6.
[http://dx.doi.org/10.1038/35037710] [PMID: 11048727]
[14]
Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: A review of the current evidence. Life Sci 2020; 254: 117717.
[http://dx.doi.org/10.1016/j.lfs.2020.117717] [PMID: 32339541]
[15]
Wen X, Lin ZQ, Liu B, Wei YQ. Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer. Cell Prolif 2012; 45(3): 217-24.
[http://dx.doi.org/10.1111/j.1365-2184.2012.00814.x] [PMID: 22429822]
[16]
Engel T, Henshall DC. Apoptosis, Bcl-2 family proteins and caspases: The ABCs of seizure-damage and epileptogenesis? Int J Physiol Pathophysiol Pharmacol 2009; 1(2): 97-115.
[PMID: 21383882]
[17]
Liu Z, Zhang G, Huang S, et al. Induction of apoptosis in hematological cancer cells by dorsomorphin correlates with BAD upregulation. Biochem Biophys Res Commun 2020; 522(3): 704-8.
[http://dx.doi.org/10.1016/j.bbrc.2019.11.157] [PMID: 31787232]
[18]
Wang Y, Su W, Mai Z, et al. Co-expression of Mcl-1 and Bak induces mitochondrial swelling. Biochem Biophys Res Commun 2020; 527(4): 866-73.
[http://dx.doi.org/10.1016/j.bbrc.2020.04.154] [PMID: 32430171]
[19]
Ludwig LM, Roach LE, Katz SG, LaBelle JL. Loss of BIM in T cells results in BCL-2 family BH3-member compensation but incomplete cell death sensitivity normalization. Apoptosis 2020; 25(3-4): 247-60.
[http://dx.doi.org/10.1007/s10495-020-01593-6] [PMID: 31993851]
[20]
Gayle SS, Sahni JM, Webb BM, et al. Targeting BCL-xL improves the efficacy of bromodomain and extra-terminal protein inhibitors in triple-negative breast cancer by eliciting the death of senescent cells. J Biol Chem 2019; 294(3): 875-86.
[http://dx.doi.org/10.1074/jbc.RA118.004712] [PMID: 30482844]
[21]
Gonzalez-Ramella O, Ortiz-Lazareno PC. Jiménez-López X, et al. Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia. Clin Transl Oncol 2016; 18(4): 369-74.
[http://dx.doi.org/10.1007/s12094-015-1376-x] [PMID: 26329293]
[22]
Huang J, Zhao D, Liu Z, Liu F. Repurposing psychiatric drugs as anti-cancer agents. Cancer Lett 2018; 419: 257-65.
[http://dx.doi.org/10.1016/j.canlet.2018.01.058] [PMID: 29414306]
[23]
Kirtonia A, Gala K, Fernandes SG, Pandya G, Pandey AK, Sethi G. Eds. Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics. Semin Cancer Biol 2021; 68(1): 258-78.
[24]
Meza-Arroyo J, Bravo-Cuellar A, Jave-Suárez LF, et al. Pentoxifylline added to steroid window treatment phase modified apoptotic gene expression in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2018; 40(5): 360-7.
[http://dx.doi.org/10.1097/MPH.0000000000001152] [PMID: 29683943]
[25]
Mansourian M, Nasab RR, Hassanzadeh F, Shahlaei M. Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in silico and in vitro cytotoxicity methods. Res Pharm Sci 2018; 13(6): 509-22.
[http://dx.doi.org/10.4103/1735-5362.245963] [PMID: 30607149]
[26]
Project E, Nachliel E, Gutman M. Force field-dependent structural divergence revealed during long time simulations of Calbindin d9k. J Comput Chem 2010; 31(9): 1864-72.
[PMID: 20033912]
[27]
Siva R, Priya R, Sumitha R, et al. Molecular docking and molecular dynamics to identify a novel human immunodeficiency virus inhibitor from alkaloids of Toddalia asiatica. Pharmacogn Mag 2015; 11(44): 414.
[http://dx.doi.org/10.4103/0973-1296.168947] [PMID: 26929575]
[28]
Ma B, Duan X, Zhou Q, et al. Use of aspirin in the prevention of colorectal cancer through TIGITCD155 pathway. J Cell Mol Med 2019; 23(7): 4514-22.
[http://dx.doi.org/10.1111/jcmm.14332] [PMID: 31090213]
[29]
Hashemi N. die-a review. Rashidian A, et al. Anti-proliferative and apoptotic effects of valproic acid on HeLa cells. Int J Cancer Manag 2022; 15(5)
[http://dx.doi.org/10.5812/ijcm-120224]
[30]
Yudhani RD, Astuti I, Mustofa M, Indarto D, Muthmainah M. Metformin modulates cyclin D1 and P53 expression to inhibit cell proliferation and to induce apoptosis in cervical cancer cell lines. Asian Pac J Cancer Prev 2019; 20(6): 1667-73.
[http://dx.doi.org/10.31557/APJCP.2019.20.6.1667] [PMID: 31244286]
[31]
Zhang Y, Feng X, Li T, Yi E, Li Y. Metformin synergistic pemetrexed suppresses non-small-cell lung cancer cell proliferation and invasion in vitro. Cancer Med 2017; 6(8): 1965-75.
[http://dx.doi.org/10.1002/cam4.1133] [PMID: 28719077]
[32]
Mishra AK, Dingli D. Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells. Leukemia 2019; 33(11): 2695-709.
[http://dx.doi.org/10.1038/s41375-019-0470-4] [PMID: 30988378]
[33]
Rizvi F, Alam M, Asad F. Promising role of metformin in reducing the viability of breast cancerous cells. Pak J Pharm Sci 2020; 33(2): 543-9.
[PMID: 32276896]
[34]
Zhao Y, Zeng X, Tang H, Ye D, Liu J. Combination of metformin and paclitaxel suppresses proliferation and induces apoptosis of human prostate cancer cells via oxidative stress and targeting the mitochondria dependent pathway. Oncol Lett 2019; 17(5): 4277-84.
[http://dx.doi.org/10.3892/ol.2019.10119] [PMID: 30944622]
[35]
Saeed HK, Sutar Y, Patel P, et al. Synthesis and characterization of lipophilic salts of metformin to improve its repurposing for cancer therapy. ACS Omega 2021; 6(4): 2626-37.
[http://dx.doi.org/10.1021/acsomega.0c04779] [PMID: 33553880]
[36]
Wang Y, Xu W, Yan Z, et al. Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res 2018; 37(1): 63.
[http://dx.doi.org/10.1186/s13046-018-0731-5] [PMID: 29554968]
[37]
Liang X, Kong P, Wang J, Xu Y, Gao C, Guo G. Effects of metformin on proliferation and apoptosis of human megakaryoblastic Dami and MEG-01 cells. J Pharmacol Sci 2017; 135(1): 14-21.
[http://dx.doi.org/10.1016/j.jphs.2017.08.003] [PMID: 28927780]
[38]
Gao ZY, Liu Z, Bi MH, et al. Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med 2016; 11(5): 1700-6.
[http://dx.doi.org/10.3892/etm.2016.3143] [PMID: 27168791]
[39]
Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M, Gotlieb WH. Induction of apoptosis by metformin in epithelial ovarian cancer: Involvement of the Bcl-2 family proteins. Gynecol Oncol 2011; 121(3): 492-8.
[http://dx.doi.org/10.1016/j.ygyno.2011.02.021] [PMID: 21388661]
[40]
Li X, Li B, Ni Z, et al. Metformin synergizes with BCL-XL/BCL-2 inhibitor ABT-263 to induce apoptosis specifically in p53-defective cancer cells. Mol Cancer Ther 2017; 16(9): 1806-18.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0763] [PMID: 28533436]
[41]
Basu A. The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy. Pharmacol Ther 2022; 230: 107943.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107943] [PMID: 34182005]

Rights & Permissions Print Cite
Article Metrics
22
4
© 2024 Bentham Science Publishers | Privacy Policy