Inhibition of autophagy potentiates anticancer property of 20(S)-ginsenoside Rh2 by promoting mitochondria-dependent apoptosis in human acute lymphoblastic leukaemia cells

Abstract

Acute lymphoblastic leukaemia (ALL) is the most prevalent childhood malignancy. Although most children with ALL are cured, there is still a group of patients for which therapy fails owing to severe toxicities and drug resistance. Ginsenoside Rh2 (GRh2), a major bioactive component isolated from Panax ginseng, has been shown to have a therapeutic effect on some tumors. However, the molecular mechanisms of cell death induced by 20(S)-GRh2 in ALL cells remains unclear. In this study, we showed that 20(S)-GRh2 inhibited the cell growth and induced mitochondria-dependent apoptosis and autophagy. But it has no cytotoxic effect on human normal blood cells. Furthermore, autophagy plays a protective role in 20(S)-GRh2-induced apoptosis in ALL cell lines and human primary ALL cells. We demonstrated that either genetic or pharmacologic inhibition of autophagy could be more effective in reducing viability and enhancing 20(S)-GRh2-induced toxicity than 20(S)-GRh2 treatment alone. In addition, inhibition of autophagy could aggravate mitochondrial ROS generation and mitochondrial damage, and then accelerate mitochondria-dependent apoptosis. Taken together, these results suggest that inhibition of autophagy can sensitize ALL cells towards 20(S)-GRh2. The appropriate inhibition of autophagy could provide a powerful strategy to increase the potency of 20(S)-GRh2 as a novel anticancer agent for ALL therapy.

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

“…Finally, inhibition of the autophagy (mitophagy), which aggravates the mitochondrial damage and potentiating mitoROS production and mitochondria‐mediated apoptosis, sensitizes ALL to anticancer chemotherapy …”

“…Finally, inhibition of the autophagy (mitophagy), which aggravates the mitochondrial damage and potentiating mitoROS production and mitochondria-mediated apoptosis, sensitizes ALL to anticancer chemotherapy. 124 promoting Ca 2+ overload, mPTP formation, and apoptosis induction. In all cases, of a good choice would be a synergistic combination of differently targeted mitocans and/or mitocans with other anti-cancer drugs (e.g., glucocorticoids), thus, increasing the sensitivity to the latter.…”

Cellular stress response mechanisms as therapeutic targets of ginsenosides

“…Numerous ginsenosides have been reported to be important regulators of autophagy and exert various biological activities either by inducing autophagy or by inhibiting autophagy. The ginsenosides that serve as autophagy inducer include CK, Rg3, Rh2, Rg1, Rg2, and F2 . Meanwhile, the ginsenosides that can inhibit autophagy include Ro, Rg3, Rg1, and Rb1 (Fig.…”

“…Ro as a novel autophagy suppressor, enhanced 5‐fluorouracil (5‐Fu)‐induced DNA damage and sensitized chemoresistant esophageal cancer cells to 5‐Fu‐mediated cell death . Interestingly, autophagy can even provide a survival advantage in 20( S )‐Rh2‐treated acute lymphoblastic leukemia (ALL) cells and F2‐treated breast cancer stem cells . In addition, the inhibition of autophagy could enhance the apoptotic cell death mediated by both 20( S )‐Rh2 and F2 .…”

“…Interestingly, autophagy can even provide a survival advantage in 20( S )‐Rh2‐treated acute lymphoblastic leukemia (ALL) cells and F2‐treated breast cancer stem cells . In addition, the inhibition of autophagy could enhance the apoptotic cell death mediated by both 20( S )‐Rh2 and F2 . In a special case, CK as an autophagy inducer sensitized TRAIL‐resistant colon cancer cells to TRAIL‐induced apoptosis.…”