摘要
背景与目的:传统逆转白血病多药耐药的药物由于不良反应大而限制了其在临床中的应用,进一步研究白血病多药耐药产生机制和有效逆转靶点成为攻克白血病多药耐药的关键。为此,本研究探讨LY294002[磷脂酰肌醇-3-激酶(PI3-K/Akt)通路抑制剂]对人类白血病K562细胞多药耐药的逆转作用。方法:锥虫蓝拒染法测定细胞生长增殖。Western印迹检测K562/S和K562/D细胞中P-gp及p-Akt的表达。流式细胞术检测细胞内药物积聚。结果:K562/D细胞对柔红霉素(DNR)、多柔比星(ADR)、长春新碱(VCR)、依托泊苷(vP16)交叉耐药,相对其亲本细胞的耐药倍数分别为65、52、134和50。DNR诱导了K562/D细胞的P-gp、p-Akt过度表达。LY294002使K562/D细胞内药物积聚增加,部分逆转了K562/D细胞对DNR、ADR、VCR、VP16的耐药性(相对耐药倍数降至23、21、63和29),而对敏感细胞K562/S的耐药性无影响。结论:LY294002部分逆转K562/ D细胞的多药耐药,可能于DNR诱导K562/D细胞的P-gp、p-Akt过度表达而LY294002抑制PI3-K/Akt信号转导通路有关。
Background and purpose： Remarkable advances have been made in cancer chemotherapy by developing new anticancer drugs and therapy strategies. However, multidrug resistance in human cancers remains a major clinical challenge for cancer treatment. Attempts in several clinical studies to reverse multidrug resistance protein （MDR） by using MDR modulators have not yet generated promising results. Our aim was to explored the mechanism of reversal of multidrug resistance in human leukemia K562 cells by PI3-K inhibitor. Methods： Trypanblue dye exclusion method was used to observe the drug sensitivity and the effect of LY294002 on the drug resistance. Western blot to analyze P-gp and p-Akt phenotypes, and flow cytometer was used to measure the intracellular drug accumulation. Results： K562/D induced by DNR was cross resistant to DNR, ADR, VCR and VP16 （Resistance Index： 65,52,134 and 50 respectively）. DNR induced over-expressions of P-gp and p-Akt in K562/D cells; LY294002 increased the intracellular drug accumulation, and then reversed the drug resistance to DNR, ADR, VCR and VP16 in K562/D cells（Resistance Index： 23, 21, 63 and 29 respectively）, but not in the sensitive cells （K562/S）. Conclusion： The multidrug resistance of K562/D cells can be induced by DNR which is related to the P-gp and p-Akt over-expressions, and LY294002 can reverse multidrug resistance in human leukemia cells in vitro via inhibits PI3-K/Akt pathway.
出处
《中国癌症杂志》
CAS
CSCD
2008年第11期844-846,共3页
China Oncology
基金
国家自然科学基金资助项目(No:30770993)
辽宁省科技攻关计划(No:2004225004-11)
