Berberine Induces Apoptosis in Acute Lymphoblastic Leukemia Cells through Downregulation of the MDM2 Oncoprotein.

Abstract

Berberine, an isoquinoline alkaloid derived from a plant used in Chinese herbal medicine, has a wide range of biological and pharmacological activities that include anti-proliferative and pro-apoptotic effects on human cancer. However, the mechanism of berberine's anticancer action is not clearly defined. Herein, we report that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells through downregulation of the MDM2 oncoprotein. In studying a set of ALL cell lines, we found that the cytotoxic and apoptotic effects of berberine were positively associated with the expression levels of MDM2 by those cells, regardless of their p53 status. However, most potent apoptosis induced by berberine was seen in ALL cells with wild-type (wt) p53 and MDM2 overexpression, while no pro-apoptotic effect of berberine was detected in MDM2-negative ALL cells that had a p53-null phenotype. Berberine induced apoptosis in wt-53/MDM2-overexpressing cells through downregulation of MDM2 and a concomitant stabilization of p53, with induction of its pro-apoptotic target PUMA. This berberine-induced p53 activation in the wt-p53/MDM2-overexpressing ALL differed from that induced by the chemotherapeutic drug doxorubicin, which activates p53 without prior MDM2 downregulation or even with a late upregulation of MDM2 due to a p53-mediated increase in transcription. The berberine's downregulation of MDM2 in ALL cells occurred at the post-translational level through modulation of DAXX, which promotes MDM2 self-ubiquitination. Because wt-p53/MDM2-overexpressing ALL cells are commonly chemo-resistant due to MDM2-regulated repression of the p53 function, the potent killing of these cells by berberine through direct targeting of MDM2 suggests that this agent may be a novel therapeutic for refractory ALL.