PHORBOL 12-MYRISTATE 13-ACETATE (PMA) INDUCES NEUROENDOCRINE-LIKE DIFFERENTIATION AND REVERSES DOXORUBICIN-RESISTANCE OF HUMAN COLON-CARCINOMA CELLS IN-VITRO
Cattedra di Oncologia Medica, Facolta di Medicina, Universita 'Federico II' di Napoli, Via S.Pansini n.5, 80131 Napoli, Italy
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Human colon carcinoma LoVo/DX cells, which have been selected from parental LoVo for resistance to doxorubicin, express a typical multidrug resistant (MDR-1) phenotype. We have investigated whether phorbol 12-myristate 13-acetate (PMA) which often induces phenotypical changes in human tumor cells could, at the same time, modulate differentiation and sensitivity of LoVo/DX cells to doxorubicin. After 48 h exposure to 100 nM PMA, morphological changes became evident on LoVo/DX cells which showed elongated cytoplasm and dendritic-like structures: moreover immunocytochemical findings were suggestive of neuroendocrine-like differentiation. Under the same experimental conditions, LoVo/DX became sensitive to doxorubicin and showed enhanced intracellular drug-accumulation and reduced membrane expression of the 170 kD glycoprotein GP-170, which is the cellular product of the mdr1 gene. We conclude that pharmacological induction of tumor cell differentiation by PMA is paralleled by abrogation of drug resistance in a colon carcinoma MDR-1 cell line.
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