Abstract
<jats:p>The current research work reports the effect of inhibition of LDH (Lactate dehydrogenase) and TGF-β (Transforming growth factor-β) on the metastatic progression of hypoxic mammary gland carcinoma. Using in silico docking studies, Ellagic acid was selected as the inhibitor of LDH, and DITU-1 (a novel compound) as the TGF-β inhibitor. In Vitro anti-cancer potential of both compounds was evaluated in MDA-MB-321 cell lines. DITU-1 and ellagic acid exhibited significant apoptotic potential as evidenced by Anexin V/FIT assay and comet assay. The anti-cancer potential of DITU-1 and ellagic was further validated through in vivo studies. Experimental mammary gland carcinoma was induced in the female SD rats with 7,12-Dimethybenzanthracenes (DMBA-50mg/i.p), and animals were grouped into Normal, toxic control and treatment groups and treated with DITU-1 and ellagic acid combination therapy. A significant increase in tumor size was observed in toxic control animals, which was reduced significantly with combination therapy of DITU-1 and ellagic acid. An increase in angiogenesis was observed through Carmine staining, which was prevented by the combination therapy at low and high doses. Combination therapy also worked well to return to normal, as confirmed by the H-NMR serum metabolic. SEM and Histopathological examination of mammary gland tissue evidenced the protective effect of the combination therapy in retaining the tissue architecture. Immunohistochemistry of HIF-1α, LDH, TGF-β, Vimentin, VEGF and MMP-9 confirmed the anti-metastatic potential of combination therapy at the molecular level. The findings of the current research report that DITU-1 and ellagic acid combination therapy can prevent metastatic progression of hypoxic mammary gland carcinoma.</jats:p>