Study On The Mechanisms Of Arsenic Trioxide (As₂O₃) Induced Apoptosis Of Retinoic Acid Resistant Acute Promyelocytic Leukemia MR2 Cells.

As the result of drugresistance(DR) mediated by various mechanisms on tumor cells, the low release rate and high relapse rate are often obtained after the leukemic chemotherapy. The DR of resistant tumor cells first lies on the resistance of apoptosis induced by chemotherapy. How to overcome the DR of Leukemic cells is the key problem of improving release rate and reducing relapse.Recently,Use of arsenic trioxide (As2O3) in the treatment of drug resistant acute promyelocytic leukemia(APL)has achieved signifcant effects.And As2O3 can induce the apoptosis of drug resistant APL.But the mechanisms of As2O3-induced drug resistant APL are remain unclear now. In order toinvestigate the possible mechanisms of As2O3-induced drug resistant APL apoptosis,APL cell line MR2 resistanted to retinoic acid(RA) was used for in vitro studies and APL cell line NB4 was used for control. The effects that As2O3-induced apoptosis of RA resistant APL and influences on expressions of P-glycoprotein(Pgp), topoisomerase II a and topoisomerase II P was observed by using flow cytometryN DNA delectrophoresis and immuno cytochemical assays. RESULT:1 . 0.25~2.0mol/L As2O3 can significantly induce apoptosis of RA resistent MR2 cell and RA senstive NB4 cell in dose梐nd time梔ependent way.2. Pgp expression rates are Significantly higher in MR2 cell Iine(mean2.1510 +1.0180) than in NB4 cell line (mean0.9447 + 0.2493) (P<0.0001).3. The expressions of DNA topoisomerase lip (topo II P) in MR2 cell line (mena30. 9542 + 11.4998) are Significantly lower in NB4 cell Iine(mean36.8514 + 8.4708) (P<0.0001).4. 0. 25~2. Onmol/L As2O3 can significantly decrease the Pgp expressions and 0. 5~2. Opimol/LAs2O3 can significantly increase topo II (3 expressions in MR2 cell line , 1. 0praol/L As2O3 can significantly decrease the Pgp expressions and 1. 0~2.0nmol/L As2O3 can significantly increasetopo II P expressions in NB4 cell line (P<0.05). The decreased Pgp expressions and the increased topo II P expressions in MR2 cell line in dose-dependent way and in time dependent way. But The decreased Pgp expressions and the increased topo II p expressions in NB4 cell line in dose-dependent way and not in time dependent way.5 . As2O3 doesn't influence upon topo II a expressions.These results show that As2O3 can induce apoptosis of RA resistant MR2 cell and RA sensitive NB4 cell.The lower expressions of topo II P and higier expressions of Pgp might take part in the RA resistant leukemia mechanisms. As2O3 can contrary APL cell risistant to RA through decreasing the Pgp expressions and increasing topo II p expressions. To regulate the expressions of topo II P and of Pgp might be one of the mechanisms of As2O3 induced MR2 cell apoptosis.