Exploitation of drug-induced Bcl-2 overexpression for restoring normal apoptosis function: A promising new approach to the treatment of multidrug resistant cancer

Su, Yaming; Zhang, Xiaoping; Sinko, Patrick J.

doi:10.1016/j.canlet.2007.01.018

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Volume 253, Issue 1 , Pages 115-123, 8 August 2007

Exploitation of drug-induced Bcl-2 overexpression for restoring normal apoptosis function: A promising new approach to the treatment of multidrug resistant cancer☆

Yaming Su
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
Xiaoping Zhang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
Patrick J. Sinko
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
- The Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Corresponding author. Address: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. Tel.: +1 732 445 3831x213; fax: +1 732 445 4271.

Received 28 September 2006; received in revised form 16 January 2007; accepted 18 January 2007.

Abstract

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 (Δψ_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.

Keywords: Multidrug resistance, Camptothecins, Acute lymphoblastic leukemia, Bcl-2, Bcl-2 inhibitor