NOXA as Target for the Combination Therapy of Betulinic Acid and Conventional Cytotoxic Drugs

Betulinic acid is a natural compound isolated from birch trees and might represent a new anti-cancer drug to treat pediatric tumors including leukemias. Here we found that Betulinic acid sensitized tumor cells for apoptosis induction by conventional cytotoxic drugs such as doxorubicin, asparaginase and vincristine. When Betulinic acid and conventional cytotoxic drugs were combined, apoptogenic factors were released from mitochondria like Cytochrome c, Smac and OMI/HtrA2 and enhanced caspase activation and DNA-fragmentation. Upon combinatorial treatment, p53 was activated and NOXA upregulated. Knockdown of either p53 or NOXA disabled synergistic apoptosis induction. Most importantly and beyond tumor cell lines, we tested primary leukemia cells derived from children with acute leukemia before onset of therapy with and without amplification in NOD/SCID mice. Knockdown of either p53 or NOXA in patient-derived leukemia cells disabled both upregulation of NOXA and synergistic apoptosis induction by Betulinic acid and conventional cytotoxic drugs. Our data suggest that NOXA represents an important, p53-regulated molecular target for the combination therapy of Betulinic acid and conventional cytotoxic drugs which enables apoptosis induction, e.g., in primary, patient-derived leukemia cells.