Zhu Y-L, Cen J, Zhang Y-Y, Feng Y-D, Yang Y, Li Y-M, Huang W-L
Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China.
Arzneimittelforschung. 2012 May;62(5):236-42. doi: 10.1055/s-0031-1301344. Epub 2012 Feb 16.
Previous studies have demonstrated that the multidrug resistance modulator HZ08 has a strong multidrug resistance reversal effect in vitro and in vivo by inhibiting P-glycoprotein and multidrug resistance-associated protein 1 in K562/A02 and MCF-7/ADM cells, respectively. However, there are many other mechanisms responsible for resistance. In this study, MTT assay was used to examine the cytotoxicity and multidrug resistance reversal of HZ08 in KBV200 cells. It was also used to detect Rh123 and adriamycin accumulation in the presence of HZ08 to assess the effect on P-glycoprotein. Caspase-3 activity was analyzed under the incubation of HZ08 per se and in combination with vincristine. Results showed that HZ08 could increase the activity of caspase-3 with P-glycoprotein inhibition. Further studies revealed that HZ08 increased vincristine-induced apoptosis, characterized as an intrinsic apoptosis pathway with enhanced G2/M phase arrest, since HZ08 had an effect on the intrinsic apoptotic regulator Bcl-2 and Bax. Therefore, the outstanding reversal effect of HZ08 occurs not only through suppressing the P-glycoprotein function but also through activating the intrinsic apoptosis pathway.
先前的研究表明，多药耐药调节剂HZ08在体外和体内均具有较强的多药耐药逆转作用，它分别通过抑制K562/A02细胞中的P-糖蛋白和MCF-7/ADM细胞中的多药耐药相关蛋白1来实现。然而，还有许多其他机制导致耐药。在本研究中，采用MTT法检测HZ08对KBV200细胞的细胞毒性和多药耐药逆转作用。还利用该方法检测在HZ08存在的情况下罗丹明123和阿霉素的蓄积情况，以评估其对P-糖蛋白的影响。在单独使用HZ08以及与长春新碱联合使用的情况下分析半胱天冬酶-3的活性。结果表明，HZ08可在抑制P-糖蛋白的同时增加半胱天冬酶-3的活性。进一步的研究表明，HZ08可增强长春新碱诱导的细胞凋亡，其特征为通过增强G2/M期阻滞呈现内源性凋亡途径，因为HZ08对内源性凋亡调节因子Bcl-2和Bax有影响。因此，HZ08显著的逆转作用不仅通过抑制P-糖蛋白功能实现，还通过激活内源性凋亡途径来实现。
