The Study Of NSC606985, A New Class Of Camptothecin Analog-induced Apoptosis In Leukemic Cells In Vitro And In Vivo

malignancies. Significant advances in understanding the biologic, molecular, and cytogenetic aspects of this malignancy have been achieved in the past 20 years. Meanwhile, substantial progress is also made in the treatment of patients with AML. However, most patients remain incurable. So development of new drugs for treatment of AML is very important. As a promising new class of anticancer drugs, camptothecins have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. In the present study, for the first time, we studied the potential anti-leukemic effectiveness of NSC606985, a new class of camptothecin analog, in vitro and in vivo. Our results indicate that 1) NSC606985, at nanomolar level, can effectively induce apoptosis in AML cells NB4 and U937 and significantly inhibit the proliferation without cell death in breakpoint cluster region–Abelson murine leukemia (bcr-abl) kinase-carrying leukemic K562 cells; 2) At such low concentrations, this agent also significantly inhibits the clonogenic activity of hematopoietic progenitors from patients with AML; 3) For apoptosis induction, NSC606985 rapidly induces the proteolytic activation of protein kinase Cδ(PKCδ) with loss of mitochondrial transmembrane potential ( m) and caspase-3 activation; 4) Co-treatment with rottlerin, a PKCδ-specific inhibitor, completely blocks NSC606985-induced mitochondrial m loss and caspase-3 activation, while the...