Calcium antagonists potentiate P-glycoprotein-independent anticancer drugsin chronic lymphocytic leukemia cells in vitro

Background and Objectives. A major obstacle to the successful use of chemot herapy in the treatment of leukemia and other cancers is the emergence of d rug resistance. One of the most studied resistance mechanisms is mediated b y P-glycoprotein, which can be modulated by calcium channel blockers. Here we investigated whether the Ca2+ channel blockers verapamil and nifedipine are toxic atone and in combination with P-glycoprotein-independent anticanc er drugs against chronic lymphocytic leukemia (CLL) cells in vitro. Design and Methods. Verapamil cytotoxicity was investigated in peripheral b lood samples of 35 patients with B-cell CLL and 10 healthy control subjects . Cytotoxicity was assessed in in vitro 4-day cultures using C-14-leucine i ncorporation as an indicator of cell viability. Interactions were tested wi th Ca2+ channel blockers and cyclosporine or 7 anticancer drugs: ii) chlora mbucil, iii) 2-chlorodeoxyadenosine, (iii) cisplatin, (iv) fludarabine, [v) prednisolone, (vi) adriamycin, and (vii) vincristine. The mode of cell dea th was assessed by annexin binding and DNA ladder formation. Results. Verapamil induced dose- and time-dependent death of CLL cells in v itro. A statistically significant effect (p = 0.0085) was noted with as lit tle as 4 mu M verapamil. The mode of cell death was apoptotic as determined by annexin positivity and condensation of verapamil-treated cells. Verapam il effectively potentiated the toxicity of cyclosporine and all the antican cer drugs mentioned above. Furthermore, nifedipine, a more specific L-type calcium channel antagonist, significantly potentiated the effect of chloram bucil against CLL cells. Interpretation and Conclusions. Calcium channel blockers enhance the effect of P-glycoprotein-independent anticancer drugs remarkably. This indicates that the death signals initiated by calcium depletion and anticancer drugs together facilitate cell death. This novel finding opens a new avenue to mo dulate, by using calcium channel antagonists, the effect of traditional ant icancer drugs having different mechanisms of P-glycoprotein-independent act ion. (C)2000, Ferrata Storti Foundation.