Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-XL [(-)-gossypol] against diffuse large cell lymphoma

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