Vinblastine Acutely Sensitizes Hematopoietic Cancers to Bcl-2 Targeting Drugs

Chronic lymphocytic leukemia (CLL) characteristically maintains high levels of the anti-apoptotic protein Bcl-2, thus protecting them from apoptotic death and leading to an accumulation of mature resting B cells. Many other hematopoietic malignancies including acute promyelocytic leukemia (APL) also depend upon Bcl-2 family proteins for survival, suggesting that Bcl-2 proteins are excellent targets for anti-cancer therapies. We have previously shown that some leukemia and lymphoma cell lines undergo rapid apoptosis (≤6 h) when incubated with the microtubule disrupting agent vinblastine. Several other cell lines undergo this rapid apoptosis when vinblastine is combined with various approaches that target the anti-apoptotic proteins Bcl-2 or Mcl-1. These approaches include incubation with ABT-737 that inhibits Bcl-2 and Bcl-X, and SCH727965 (dinaciclib) that inhibits CDK7/9, thereby inhibiting translation, which results in rapid loss of Mcl-1. In this study, we have assessed the ability of these agents alone or in combination to induce apoptosis in freshly isolated CLL and APL cells. Incubation with vinblastine alone induced variable apoptosis within 6 h (5-60%). ABT-737 induced rapid and almost complete apoptosis in CLL and in 50% of APL cells ex vivo. However, when combined with vinblastine, a 10-fold lower concentration of ABT-737 was required to induce complete apoptosis. Dinaciclib alone also induced variable levels of apoptosis (5-90%), but again the combination with vinblastine induced extensive apoptosis at lower concentrations of both drugs. Normal peripheral blood mononuclear cells were resistant to single agent or combination treatments. Sensitivity to ABT-737, dinaciclib or vinblastine was independent of CD38 and ZAP70 status and previous clinical treatment (untreated or relapsed patients). These results suggest that combinations of vinblastine and ABT-737 or dinaciclib are more effective than single agent therapy. Furthermore, these combinations may overcome resistance to individual drug therapies in patients with CLL or APL.