Antiproliferative effect of ketogenic diet on hormone independent mammary gland carcinoma via harnessing glucose metabolism: In-vitro and In-vivo investigations

Abstract

The ketogenic diet (KD) has been emphasized as a complementary strategy for management of several clinical conditions including cancer. Therefore, in this study we explored the effect of KD in mammary gland carcinoma through in-vitro and in-vivo studies. In-vitro studies were performed on MCF-7 and MDA-MB-231 cells with different experimental conditions such as high glucose (HG), low glucose (LG) and no glucose(NG) in conjugation with β-hydroxy butyrate(BHB) treatment. The MTT assay revealed that glucose deprivation alongwith BHB(10 mM) treatment significantly reduces the viability of MDA-MB-231 cells as compared to MCF-7 cells. Moreover, apoptotic and antiproliferative potential (via AO/EtBr, JC-1, cell migration assay) were analyzed on MDA-MB-231 cells which indicate that NG with BHB treatment induce cell death.Furthermore, we investigated the in-vivo anticancer efficacy against DMBA-induced mammary gland carcinoma in female Wistar rats. KD treatment effectively restored autonomic dysfunction, altered mammary gland morphology and histology; as evident through decrease in lobules, alveolar bud, restoration of the surface architecture and loss of tumor micro-vessels. The altered levels of antioxidants such as TBARs(0.85 ± 0.19 nM of MDA/µg of protein), SOD(2.26 ± 0.05 U/µg of protein), PC(41.36 ± 2.94 µM/µg of protein), GSH(10.58 ± 3.08 µM/µg of protein) were also restored after KD treatment. Overall findings suggested, that deprived glucose concentration alongwith BHB can impart antiproliferative and apoptotic effect as observed through MDA-MB-231cells. Moreover, KD also diminished the carcinogenic effects of DMBA in albino wistar rats. In view of above, the KD was utilised as adjuvant therapy in the management of mammary gland carcinoma,possibly by providing unfavourable microenvironment for highly proliferating tumour cells due deficiency of quickly available glucose.