Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

Abstract

Graphical AbstractMechanism of VOA and VIN to inhibit fatty acid synthesis in DMBA-induced mammary gland carcinoma of albino Wistar rats. Hypoxia-activated HIF-1α enhances lactate acidosis in the tumor microenvironment, and dysregulated pH in the tumor microenvironment activates SREBP-1c and FASN expression to speed up the fatty acid synthesis required for plasma membrane synthesis in rapidly proliferating cells. VOA- and VIN-activated PHD-2 enhanced the proteolytic degradation of HIF, thus inhibiting fatty acid synthesis. HIF-1α, hypoxia-inducible factor-1α; SREBP-1c, sterol regulatory element-binding protein-1c; FASN, fatty acid synthesis; PHD-2, prolyl hydroxylase-2.