Exploitation of drug-induced Bcl-2 overexpression for restoring normal apoptosis function: a promising new approach to the treatment of multidrug resistant cancer.
Agents antagonizing the anti-apoptotic Bcl-2 protein have been shown to restore normal apoptotic processes in cancer cells. Since upregulation of Bcl-2 is often observed in recurrent or refractory hematological malignancies, we were prompted to investigate whether drug-selected leukemia cells overexpressing Bcl-2 were more susceptible to Bcl-2 antagonists. The current study showed that a camptothecin (CPT)-selected human leukemia cell line (CPT-K5) had remarkably higher expression levels of Bcl-2 than its drug sensitive parental cell (RPMI 8402). A small molecule inhibitor of Bcl-2, HA14-1, induced much more extensive apoptosis in CPT-K5 than in RPMI 8402 cells, as characterized by DNA fragmentation, loss of mitochondrial membrane potential (Deltapsi(m)) and plasma membrane integrity, as well as the activation of caspase. Taken together, these findings suggest that small molecule Bcl-2 inhibitors may represent a promising class of alternative agents for the treatment of Bcl-2 overexpressed refractory or recurrent hematological malignancies when conventional chemotherapy fails.
Su
Yaming
Y
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Zhang
Xiaoping
X
Sinko
Patrick J
PJ
D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation; D019254:Genes, bcl-2; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D001578:Benzopyrans; D009570:Nitriles; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D020169:Caspases