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Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX

Requests for Reprints: Alakananda Basu, Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. Phone: (817) 735-2487; Fax: (817) 735-2118. E-mail: abasu{at}hsc.unt.edu

Overexpression of the anti-apoptotic protein Bcl-2 has been associated with several malignancies, including small cell lung cancer (SCLC). In the present study, we have investigated if Bcl-2 contributes to the emergence of cisplatin resistance in SCLC H69 cells. The ability of cisplatin to induce apoptosis was decreased in H69 cells that acquired resistance to cisplatin (H69/CP). The level of Bcl-2 was, however, substantially reduced in H69/CP cells compared to parental H69 cells. There was little change in Bcl-2 content in H69 cells that were resistant to etoposide (VP-16) or Taxol. Bcl-2 was constitutively phosphorylated at serine 70 in H69 cells but not in H69/CP cells and cisplatin had little effect on Bcl-2 phosphorylation. The level of procaspase-3 was elevated in H69/CP cells but the ability of cisplatin to induce mitochondrial depolarization, caspase-9 activation, and poly(ADP-ribose) polymerase (PARP) cleavage was compromised in H69/CP cells. The level of the anti-apoptotic protein Bcl-x_L and the pro-apoptotic protein Bax was slightly reduced in H69/CP cells but the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins was not sufficient to explain cellular resistance to cisplatin. These results suggest that the acquisition of cisplatin resistance by H69 cells was not due to an increase in the level/phosphorylation status of the anti-apoptotic protein Bcl-2.

Key Words: Bcl-2 • cisplatin • SCLC • drug resistance • apoptosis

Grant support: National Cancer Institute Grant CA85682 and Institutional Tobacco Research Grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Present address of S.K. Biswas: Department of Microbiology and Immunology, Health Science Center, Texas Tech University, Lubbock, TX 79430. Present address of S. Persaud: Laboratory of Neurogenetics, National Institute of Alcohol Abuse and Alcoholism, Rockville, MD 20852.

Received 5/13/03; revised 12/23/03; accepted 12/30/03.