0058
INVESTIGATION
OF THE MECHANISMS OF MULTIDRUG RESISTANCE CAUSED BY DIFFERENTIATION INDUCER LI CR, FU JR, YANG J Children Hospital of Shenzhen, Shengzhen, China Objective: To
investigate the regulatory mechanisms of multidrug resistance (MDR) caused by
differentiation inducer. Methods: All-trans
retinoic acid and IL-4 were employed to treat human hepatoblastoma cell line
(HepG2) cells. The ploliferative activity, synthesis of AFP and
cell cycle distribution of the 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
treatmemt of the tumor cells led drug resistance to chemotherapies
(Resistant factors:1.6~3), and IL-4 increased the sensitivity of the tumor
cells to antineoplasic drugs (Reversal index:4-17). The levels of P-gp
expression in ATRA-treated cells was
increased (from 54.3±8.6% up to 98.5±11.4% 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-regulated c-jun and c-myc mRAN
expression. The levels of p53 and Bcl-2 expression could be up- or
down-regulated by IL-4 treatment, but were unaffected by ATRA
treatment. Conclusion: Degree of
cell differentiation and levels of c-jun and c-myc mRNA expression might
not be related to alteration of drug sensitivity in inducing differentiaton
of HepG2 cells with ATRA and IL-4. Increased expression of P-gp
caused by ATRA might be one of factors up-regulating MDR.p53 (or
Bcl-2) might be involved in
regulating sensitivity of antineoplastic drugs in inducing differentiation. Key
words: Differentiation, inducer, Multidrug resistance, P-glycoprotein P53, Bcl-2