[Mechanism of multidrug resistance caused by retinoic acid].

OBJECTIVE

To investigate the regulatory mechanism of multidrug resistance(MDR) caused by all-trans retinoic acid (ATRA).

METHODS

ATRA and IL-4 were used to treat human hepatoblastoma cell line (HepG2) cells. The proliferative activity, synthesis of alpha fetal protein (AFP), and cell cycle distribution of tumor cells were observed to evaluate the degree of cell differentiation. Flow cytometry and in situ hybridization were used to determine the expressing levels of p53, bcl-2, P-glycoprotein (P-gp) and c-jun and c-myc mRNA. MTT assay was used to evaluate the sensitivity of the tumor cells to chemotherapeutic agents.

RESULTS

Both ATRA and IL-4 could induce the differentiation of HepG2 cells. ATRA treatment of the tumor cells led to drug resistance in chemotherapy (resistant factors: 1.6-3.1), and IL-4 increased the sensitivity of the tumor cells to antineoplasic drugs (reversal index: 4-17). The level of P-gp expression in ATRA-treated cells was increased from 54.2% +/- 8.6% up to 98.5% +/- 1.4% (P < 0.01), but IL-4 markedly inhibited expression of P-gp down to 25.4% +/- 7.3% (P < 0.01). Both ATRA and IL-4 treatment could down-regulate c-jun and c-myc mRAN expressions. The level of p53 and bcl-2 expression could be up- or down-regulated by IL-4 treatment but they were unaffected by ATRA treatment.

CONCLUSION

Degree of cell differentiation and level of c-jun and c-myc mRNA expression might not be related to change in drug sensitivity by inducing differentiation of HepG2 cells with ATRA and IL-4. Increased expression of P-gp caused by ATRA might be one of the factors up-regulating MDR. p53 (or bcl-2) might be involved in regulating the sensitivity of antineoplastic drugs by inducing differentiation.