DIFFERENTIATION OF NEUROBLASTOMA ENHANCES BCL-2 EXPRESSION AND INDUCES ALTERATIONS OF APOPTOSIS AND DRUG-RESISTANCE

Recent evidence suggests that resistance to antineoplastic therapy may result from mutations in genes mediating the apoptotic response to DN A damage, To determine the effects of epigenetic changes on tumor resp onsiveness to cytotoxic agents inducing DNA damage, we examined the ch emosensitivity of neuroblastoma (NB) after differentiation by retinoic acid (RA). Differentiation of the cell lines SH-SY5Y and SMS-KCNR by RA abolished the cytotoxic effects of adriamycin (Adr) and cisplatin. Chemoresistance was not the result of decreased proliferation induced by RA because: (a) growth arrest by nutrient deprivation did not affec t sensitivity; (b) growth arrested NE cell lines, which did not differ entiate, remained chemosensitive; and (c) RA concentrations which prom oted differentiation without affecting growth, induced resistance, Apo ptosis characterized NE cells responding to Adr, although differentiat ed SH-SY5Y did not apoptose and were resistant to Adr and cisplatin. M arked induction of bcl-2 in NE cells followed RA-induced differentiati on, whereas in cell lines failing to differentiate, bcl-2 was not dete cted, Our data indicate that NE differentiation induces drug resistanc e after a loss of the apoptotic response to antineoplastic drugs and s uggest that bcl-2 overexpression is an important mechanism of resistan ce in differentiated tumor cells.