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Biochem Pharmacol. 2018 Oct;156:322-339. doi: 10.1016/j.bcp.2018.08.041. Epub 2018 Aug 29.

Methylglyoxal at metronomic doses sensitizes breast cancer cells to doxorubicin and cisplatin causing synergistic induction of programmed cell death and inhibition of stemness.

Author information

1
Department of Biophysics, Bose Institute, P 1/12 CIT Scheme VII M, Kolkata 700 054, WB, India.
2
Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake City, Kolkata 700 098, WB, India.
3
Division of Molecular Medicine, Bose Institute, P 1/12 CIT Scheme VII M, Kolkata 700 054, WB, India. Electronic address: kuladip@jcbose.ac.in.
4
Department of Biophysics, Bose Institute, P 1/12 CIT Scheme VII M, Kolkata 700 054, WB, India; Department of Chemistry, Institute of Applied Science & Humanities GLA University Mathura, 17km Stone, NH-2, Mathura-Delhi Road, Mathura 281 406, UP, India. Electronic address: manjuray@jcbose.ac.in.

Abstract

Potent anticancer activity coupled with absence of toxicity at therapeutic dose established the glycolytic metabolite, methylglyoxal, as a promising candidate against malignant neoplasia. In this preclinical study we illustrate the applicability of methylglyoxal in formulating an optimally designed combination regimen with chemotherapeutic drugs against breast cancer. Results demonstrated a synergistic augmentation in doxorubicin and cisplatin mediated cytotoxicity in human breast cancer cell lines MDA MB 231 & MCF 7 with methylglyoxal co-treatment at metronomic concentrations. The cell death due to combination treatment was significantly prevented by N-Acetylcysteine and the synergistic effects were attenuated in presence of inhibitors for apoptosis and necroptosis, in MDA MB 231 and MCF 7 cells, respectively. Additionally, acridine orange staining and immunoblotting with LC3B antibody indicated the suppression of doxorubicin induced autophagy flux with methylglyoxal co-treatment. This report documents for the first time the preferential targeting of breast cancer stem cells by methylglyoxal. Combination treatment with doxorubicin or cisplatin hindered mammosphere forming efficiency and inclusively eliminated both cancer stem as well as non-stem cancer cells. The synergistic effect was validated in Ehrlich mammary carcinoma cell induced murine ascites model and the combination advantage in vivo was achieved without any additional deleterious effect to liver and kidney. Our present study evidences the implications of methylglyoxal inclusion in adjuvant multimodal chemotherapeutics against breast cancer and offers noteworthy insights into the possible outcome.

KEYWORDS:

Autophagy; Cancer stem cells; Combination therapy; Methylglyoxal; Reactive oxygen species

PMID:
30170097
DOI:
10.1016/j.bcp.2018.08.041
[Indexed for MEDLINE]

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