Anticancer efficacy of 2-Hydroxy-4-methoxybenzoic acid through dual regulation of lactate transport via inhibition of MCT-1 and MCT-4

Abstract

Monocarboxylate transporters (MCTs) play critical role in the progression of mammary gland carcinoma. The unregulated cell growth increased glycolytic phenotype via glycolysis pathway which leads to concomitant synthesis of lactate. Lactate facilitates acidification of tumour microenvironment (TME), metastasis, and immune evasion. Thus, MCTs inhibition has emerged as a novel approach to treat mammary gland carcinoma. Herein, the current study aim to identify and validate small molecule as dual MCT-1 and MCT-4 inhibitor for mammary gland chemoprevention. We performed structure based virtual screening of natural based library (HY-L057L) and outcomes underscore 2-Hydroxy-4-methoxybenzoic acid (HMBA) as potential compound. HMBA demonstrated higher molecular docking score, favourable ADMET profiling and drug-likeness.Moreover, HMBA was examined for its cytotoxicity and apoptotic activity via in-vitro studies on MCF-7 cells. The results showed that HMBA possessed a substantial IC50 value of 4.8 μM and having apoptotic potential. Additionally, we tested its anticancer effects against a 7,12- dimethylbenz[a]anthracene) (DMBA)-induced tumour model in-vivo. Our findings demonstrated that the HMBA effectively corrected the altered histology and morphology. The altered levels of lactate and antioxidant were also restored by HMBA. In addition, HMBA regulate the mitochondrial apoptotic pathway and inhibit the hypoxia and angiogenesis and the lactate exchange transporters proteins, according to the results of the western blotting. The overall findings obtained from in-silico, in-vitro, and in-vivo studies present strong evidence for the pre-clinical effectiveness of HMBA in treating mammary gland carcinoma through dual inhibition of MCT-1 and MCT-4 and may pave the way for more Investigational New Drug (IND) compliance testing.