Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines

Integrin-mediated adhesion influences cell survival and may prevent program med cell death. Little is known about how drug-sensitive tumor cell lines s urvive initial exposures to cytotoxic drugs and eventually select for drug- resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selecte d for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha(4)beta(1)) and VL A-5 (alpha(5)beta(1)) integrin fibronectin (FN) receptors, are relatively r esistant to the apoptotic effects of doxorubicin and melphalan when pre-adh ered to FN and compared with cells grown in suspension, This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulati on or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with eith er doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha(4)-mediated cell adhesion in both drug-resi stant variants compared with the drug-sensitive parent line. When removed f rom selection pressure, drug-resistant cell lines reverted to a drug sensit ive and alpha(4) -low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined, in conclusion, we have demonstrated that FN-mediated adhesion confers a su rvival advantage for myeloma cells acutely exposed to cytotoxic drugs by in hibiting drug-induced apoptosis. This finding may explain how some cells su rvive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression. (C) 1999 by The American Socie ty of Hematology.