This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mohammad, R. M. Articles by Al-Katib, A. Search for Related Content PubMed PubMed Citation Articles by Mohammad, R. M. Articles by Al-Katib, A.

¹ Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan and ² Departments of Internal Medicine and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Ramzi M. Mohammad, Division of Hematology and Oncology, Department of Internal Medicine/Karmanos Cancer Institute, Wayne State University School of Medicine, 724 HWCRC, 4100 John R. Street, Detroit, MI 48201. Phone: 313-966-7427; Fax: 313-966-7558. E-mail: Mohammad{at}karmanos.org

Overexpression of Bcl-2/Bcl-X_L protein has been observed in more than 80% of B-cell lymphomas. Diffuse large cell lymphoma (DLCL) is the most common subtype of non-Hodgkin's lymphoma. (–)-Gossypol, a natural product isolated from cottonseeds, was discovered as a potent small-molecule inhibitor of Bcl-2 and Bcl-X_L proteins, with a K_i value in the nanomole per liter range for both. In vitro, (–)-gossypol showed significant growth inhibition effect against WSU-DLCL₂ lymphoma cell line and fresh cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. As expected (–)-gossypol induced complete cytochrome c release from mitochondria, increased caspases-3 and -9 activity, and caused apoptotic death without affecting protein levels of Bcl-2, Bcl-X_L, Bax, and Bak. The addition of cyclophosphamide-Adriamycin-vincristine-prednisolone (CHOP) regimen to lymphoma cells preexposed to (–)-gossypol enhanced killing significantly. The maximum tolerated dose of (–)-gossypol in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg x 3 when given in combination with CHOP. Using WSU-DLCL₂-SCID mouse xenograft model, the tumor growth inhibition, the tumor growth delay, and the log₁₀ kill of mice treated with (–)-gossypol + CHOP were better than CHOP or (–)-gossypol alone. We conclude that adding Bcl-2/Bcl-X_L small-molecule inhibitor to standard chemotherapy may prove an effective strategy in lymphoma therapy.

Key Words: B cell • DLCL • nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X_L • (–)-Gossypol • Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) • Xenografts

Grant support: NIH grant P30 CA22453-20 and the Department of Defense Breast Cancer Program BC000914 (S. Wang).

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 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 1/04; revised 10/ 4/04; accepted 11/ 8/04.