Abdul Mansoor, Hoosein Naseema
Edward Via Virginia College of Osteopathic Medicine and Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
Oncol Rep. 2003 Nov-Dec;10(6):2023-6. doi: 10.3892/or.10.6.2023.
MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.
MKT-077是一种离域亲脂性阳离子，可选择性地靶向癌细胞。据报道，MKT-077可抑制多种肿瘤类型的生长，并已进行了I期临床试验。我们研究了MKT-077单独使用以及与止泻药洛哌丁胺联合使用的效果。在体外对十种人类癌细胞系进行了测试，其中包括四种前列腺癌细胞系（PC3、DU145、LNCaP、MDA-PCA-2B）、两种乳腺癌细胞系（MCF-7和MDA-MB-231）和四种结肠癌细胞系（LoVo、Colo320DM、SW1116和LS174t）。在处理前将细胞培养至汇合状态。洛哌丁胺以剂量依赖性方式增强了MKT-077在所有十种细胞系中的抗增殖作用。MDA-PCA-2B细胞系、两种乳腺癌细胞系和四种结肠癌细胞系对MKT-077的敏感性相对较低（抑制生长95%需要>2.5μg/ml的MKT-077）。在这些细胞系中，0.5-5μg/ml（1-10μM）的洛哌丁胺使对MKT-077的反应显著增加。已知洛哌丁胺在纳摩尔浓度下可激活微阿片受体，在微摩尔剂量下可阻断电压门控钙通道。我们发现钙通道阻滞剂地尔硫卓和硝苯地平（10-20μg/ml）以及他莫昔芬（1.5-2.5μg/ml）也可增强MKT-077的生长抑制作用。这些协同相互作用可用于治疗获益。
