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Betulinic Acid-induced Programmed Cell Death in Human Melanoma Cells Involves Mitogen-activated Protein Kinase Activation¹

Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612

Betulinic acid, a naturally occurring triterpene found in the bark of the white birch tree, has been demonstrated to induce programmed cell death with melanoma and certain neuroectodermal tumor cells. We demonstrate currently that treatment of cultured UISO-Mel-1 (human melanoma cells) with betulinic acid leads to the activation of p38 and stress activated protein kinase/c-Jun NH₂-terminal kinase [widely accepted proapoptotic mitogen-activated protein kinases (MAPKs)] with no change in the phosphorylation of extracellular signal-regulated kinases (antiapoptotic MAPK). Moreover, these results support a link between the MAPKs and reactive oxygen species (ROS). As demonstrated previously, cells treated with betulinic acid generate ROS. Preincubation of cells with antioxidants blocks the process of programmed cell death, and prevents the phosphorylation of p38 and stress activated protein kinase/c-Jun NH₂-terminal kinase. These data suggest that ROS act upstream of the MAPKs in the signaling pathway of betulinic acid. In addition to mediating these responses, treatment of cells with betulinic acid resulted in a gradual depolarization of mitochondrial membrane potential, a phenomenon established to contribute to the induction of programmed cell death. Interestingly, p38 was capable of partially modulating this perturbation, and investigations of mitochondria-associated apoptotic events indicate no involvement of known caspases. These data provide additional insight in regard to the mechanism by which betulinic acid induces programmed cell death in cultured human melanoma cells, and it likely that similar responses contribute to the antitumor effect mediated with human melanoma carried in athymic mice.

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