Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications

A natural product betulinic acid (BA) has gained a huge significance in the recent years for its strong cytotoxicity. Surprisingly, in spite of being an interesting cancer protecting agent on a variety of tumor cells, the normal cells and tissues are rarely affected by BA. Betulinic acid and analogues (BAs) generally exert through the mechanisms that provokes an event of direct cell death and bypass the resistance to normal chemotherapeutics. Although the major mechanism associated with its ability to induce direct cell death is mitochondrial apoptosis, there are several other mechanisms explored recently. Importantly, mathematical modeling of apoptosis has been an important tool to explore the precise mechanism involved in mitochondrial apoptosis. Thus, this review is an endeavor to sum up the molecular mechanisms underlying the action of BA and future directions to apply mathematical modeling technique to better understand the precise mechanism of BA-induced apoptosis. The last section of the review encompasses the plausible structural modifications and formulations to enhance the therapeutic efficacy of BA.