ANTIPROLIFERATIVE AND APOPTOGENIC EFFICACY OF ANTIDIABETIC DRUGS METFORMIN AND SITAGLIPTIN AGAINST MCF7 AND HEPG2 CANCER CELLS: A COMPARATIVE MOLECULAR STUDY

Mrinmoy Sarkar, Sananda Dey, Biplab Giri

Abstract


Lifestyle and diet-related disorder type 2 diabetes (T2D), has reached epidemic margin globally. The relationships between diabetes and cancer are complex. However, evidence supports the hypothesis that obesity raises the risks of both T2D and certain cancers. A further complication arises from the controversy that drugs used in the treatment of T2D increase or decrease cancer risk or influence cancer diagnosis. Herein, we hypothesized that the antidiabetic medications can improve cancer outcome. In this study, we have studied the potency and efficacy of two well-known antidiabetic drugs metformin and sitagliptin. Although there are controversies for the usage of DDP4 inhibitors, we found that sitagliptin has a potent cytotoxic effect on both type of cancer cells (MCF7 and HepG2). It has also shown certain impact on early apoptogenic efficacy in HepG2 and late apoptogenic efficacy on MCF7 as well as the caspase-3 activity expression in both cell lines. In the line of our study, it might be concluded that sitagliptin has significant antiproliferative and apoptogenic efficacy in MCF7 and HepG2 cancer cells, though it was observed to be lesser than that of metformin. Further thorough investigation in a cancer-diabetes animal model, as well as the trial on cancer-diabetic human subjects, is required to establish the efficacy of type 2 antidiabetic drugs in treating diabetic cancer patients.

Keywords: Metformin; Sitagliptin; DPP4 inhibitor; Cancer; Diabetes; Proliferation;  Apoptosis;


References


Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D, Diabetes and cancer: a consensus report, Diabetes Care, 2010, 33(7), 1674-1685.

Feng S, Cokus SJ, Zhang X, Chen PY, Bostick M, Goll MG, Hetzel J, Jain J, Strauss SH, Halpern ME, Ukomadu C, Sadler KC, Pradhan S, Pellegrini M, Jacobsen SE, Conservation and divergence of methylation patterning in plants and animals, Proc Natl Acad Sci U S A, 2010, 107(19), 8689-94.

Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy, Annals of Translational Medicine, 2014, 2(6), 57.

Chang TH, Szabo E, Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer, Cancer Res, 2000, 60(4), 1129-1138.

Kole L, Sarkar M, Deb A, Giri B, Pioglitazone, an anti-diabetic drug requires sustained MAPK activation for its anti-tumor activity in MCF7 breast cancer cells, independent of PPAR-γ pathway, Pharmacol Rep, 2016, 68(1), 144-154.

Lambeir AM, Scharpé S, De Meester I, DPP4 inhibitors for diabetes--what next? Biochem Pharmacol, 2008, 76(12), 1637-1643.

Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH, The role of CD26/dipeptidyl peptidase IV in cancer, Front Biosci, 2008, 13, 1634-1645.

Ozóg J, Jarzab M, Pawlaczek A, Oczko-Wojciechowska M, Włoch J, Roskosz J, Gubała E, Expression of DPP4 gene in papillary thyroid carcinoma, Endokrynol Pol, 2006, 57, Suppl A, 12-17

Wesley UV, McGroarty M, Homoyouni A, Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway, Cancer Res, 2005, 65(4), 1325-1334.

Ghosh S, Mukhopadhyay S, Sarkar M, Mandal A, Das V, Kumar A, Giri B, Biological evaluation of a halogenated triterpenoid, 2α-bromo-dihydrobelulonic acid as inhibitor of human topoisomerase IIα and HeLa cell proliferation, Chem Biol Interact, 2017, 268, 68-76.

Chazotte B. Labeling nuclear DNA with Hoechst 33342. Cold Spring Harb Protoc 2011.

Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC, Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies, Gastroenterology, 2011, 141(1),150-156.

Nelson M, Bhandari N, Wener J, Sitagliptin-induced pancreatitis – a longer road than expected, Clin Case Rep, 2014, 2(4), 149-152.

Faillie JL, Yu OH, Yin H, Hillaire-Buys D, Barkun A, Azoulay L, Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus, JAMA Intern Med, 2016, 176(10), 1474-1481.

Hegedus L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH, GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide, J Clin Endocrinol Metab, 2011, 96(3), 853–860.

Tseng CH. Sitagliptin use and thyroid cancer risk in patients with type 2 diabetes, Oncotarget, 2016, 7(17), 24871-24879.

Sarkar M, Dey S, Giri B, Double Edge Effect of DPP4 Inhibitor Sitagliptin, A Type-2 Anti-Diabetic Drug, on Inflammation, Injury and Cancer, J Stem Cell Regen Biol, 2017, 3(1), 1- 7.

Sliwinska A, Rogalska A, Marczak A, Kasznicki J, Drzewoski J, Metformin, but not sitagliptin, enhances WP 631-induced apoptotic HepG2 cell death, Toxicol In Vitro, 2015, 29(5), 1116-1123.

Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS, Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity, PLoS One, 2017, 12(3), 1-16.

Wang XM, Yang YJ, Wu YJ, Zhang Q, Qian HY, Attenuating Hypoxia-Induced Apoptosis and Autophagy of Mesenchymal Stem Cells: the Potential of Sitagliptin in Stem Cell-Based Therapy, Cell Physiol Biochem, 2015, 37, 1914-1926.

Tseng C-H, Sitagliptin may reduce prostate cancer risk in male patients with type 2 diabetes, Oncotarget, 2017, 8(12),19057-19064.

Tseng C-H, Sitagliptin May Reduce Breast Cancer Risk in Women With Type 2 Diabetes, Clin Breast Cancer, 2017, 17(3), 211-218.

Choi HJ, Kim JY, Lim S, Kim G, Yun HJ, Choi HS, Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression, British J Pharmacol, 2015, 172(21), 5096-5109.


Full Text: PDF

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

footer_848
ISSN: 2250-1177  This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License.