Angoline inhibits breast cancer cell proliferation and induces autophagy related cell death via attenuating lactate dehydrogenase A activity

Dysregulated metabolism is one of the major hallmarks of malignant tumors, which includes increased glycolysis even in the presence of ample oxygen, providing a metabolic advantage for cell proliferation and tumor growth. Recognition of metabolic reprogramming in oncogenesis has paved the way for developing novel therapeutic approaches and agents targeting the key enzymes involved in this process. The therapeutic potential of plant-derived natural bioactive compounds is promising, due to their diverse structures and multiple targets. Angoline, an isoquinoline alkaloid isolated, has been reported to inhibit cancer cell proliferation and tumor growth, but the underlying mechanisms remain largely unclear. Our results showed that Angoline effectively inhibits breast cancer cell proliferation and tumor growth. Mechanistically, angoline directly binds to LDHA and suppresses its activity, resulting in decreased glycolytic rates, less lactate production and increased oxygen consumption in breast cancer cells. Furthermore, the metabolic switch from aerobic glycolysis to oxidative phosphorylation by angoline treatment induces the accumulation of intracellular ROS, which in turn causes a decline in mitochondrial membrane potential and subsequently triggers autophagy. In vivo xenograft model further confirmed the efficacy and safety of angoline in breast cancer treatment. Together, these results suggested that Angoline is a promising natural compound to inhibit LDHA activity, leading to decreased glycolytic rate and increased autophagy related cell death in breast cancer cells. These data together reveal an underlying molecular mechanism of angoline to treat breast cancer.