SUPPRESSION OF ANTI-MICROTUBULE AGENT-INDUCED APOPTOSIS BY NITRIC-OXIDE - POSSIBLE MECHANISM OF A NEW DRUG-RESISTANCE

The propensity of a cell to undergo apoptosis has been proposed to be a determinant of sensitivity to anti-microtubule agents. The anti-micr otubule agents vincristine and paclitaxel induce key features of apopt osis, such as intranucleosomal DNA fragmentation and changes in nuclea r morphology in the human neuroblastoma cell line, NB-39-nu. Nitric ox ide (NO) generated from NO-releasing drugs prevented anti-microtubule agent-induced apoptosis in this cell line. The mechanism of suppressio n of apoptosis by NO appears to be via the inhibition of an interleuki n-1 beta converting enzyme-like protease cascade. This finding reveals a new biological function of NO, as well as a new molecular insight i nto resistance to chemotherapy with anti-microtubule agents.