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ARTICLE

Anti-cancer effects of sitagliptin, vildagliptin, and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

POOJA JAISWAL¹, VERSHA TRIPATHI¹, ANSHUL ASSAIYA², DHARMENDRA KASHYAP³, RAHUL DUBEY⁴, ANAMIKA SINGH⁴, JANESH KUMAR², HEM CHANDRA JHA³, RAJESH SHARMA⁵, AMIT KUMAR DIXIT⁶, HAMENDRA SINGH PARMAR^1,*

1 School of Biotechnology, Devi Ahilya University, Indore, 452001, India
2 Laboratory of Membrane Protein Biology, National Centre for Cell Science, Pune, 411007, India
3 Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, 452020, India
4 Department of Biotechnology, IPS Academy, Indore, 452012, India
5 School of Pharmacy, Devi Ahilya University, Indore, 452001, India
6 Central Council for Research in Ayurvedic Sciences, Kolkata, 263645, India

* Corresponding Author: HAMENDRA SINGH PARMAR. Email:

(This article belongs to the Special Issue: Mitochondrial Signaling and Metabolism in Cancer)

BIOCELL 2022, 46(12), 2645-2657. https://doi.org/10.32604/biocell.2022.021754

Received 02 February 2022; Accepted 13 April 2022; Issue published 10 August 2022

Abstract

Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria. On the other hand, dipeptidyl peptidase-IV (DPP-IV) inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis, but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line. We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase (AMPK), which activates the downstream transcription factors PGC-1α, PGC-1β, or FOXO1 for mitochondrial biogenesis; above-mentioned incretin-based therapies are also known to activate AMPK. This study evaluated the effects of sitagliptin, vildagliptin, and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis, were examined. Treatment with sitagliptin (100 µM), vildagliptin (100 µM), and exendin-4 (10 nM) for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay, cell migration by scratch, and transwell migration assays, accompanied with marginal reduction in cell numbers along with the apoptotic appearance, the rate of apoptosis, and decreased lactate content in conditioned medium. These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio, increased MitoTracker green and red staining, and increased expression of transcription factors PGC-1α, NRF-1, NRF-2, TFAM, and HO-1. Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1 µM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay. Thus, sitagliptin, vildagliptin, and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect. Therapeutic response was in the order of: sitagliptin > vildagliptin > exendin-4.

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