PHORBOL 12-MYRISTATE 13-ACETATE (PMA) INDUCES NEUROENDOCRINE-LIKE DIFFERENTIATION AND REVERSES DOXORUBICIN-RESISTANCE OF HUMAN COLON-CARCINOMA CELLS IN-VITRO

Human colon carcinoma LoVo/DX cells, which have been selected from par ental LoVo for resistance to doxorubicin, express a typical multidrug resistant (MDR-1) phenotype. We have investigated whether phorbol 12-m yristate 13-acetate (PMA) which often induces phenotypical changes in human tumor cells could, at the same time, modulate differentiation an d sensitivity of LoVo/DX cells to doxorubicin. After 48 h exposure to 100 nM PMA, morphological changes became evident on LoVo/DX cells whic h showed elongated cytoplasm and dendritic-like structures: moreover i mmunocytochemical findings were suggestive of neuroendocrine-like diff erentiation. Under the same experimental conditions, LoVo/DX became se nsitive to doxorubicin and showed enhanced intracellular drug-accumula tion and reduced membrane expression of the 170 kD glycoprotein GP-170 , which is the cellular product of the mdr1 gene. We conclude that pha rmacological induction of tumor cell differentiation by PMA is paralle led by abrogation of drug resistance in a colon carcinoma MDR-1 cell l ine.