title: Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen.
abstract: 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.
authors.affiliation: Edward Via Virginia College of Osteopathic Medicine and Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Abdul
authors.forename: Naseema
authors.initials: N
authors.lastname: Hoosein
mesh_terms: D000930:Antidiarrheals / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002412:Cations; D002455:Cell Division; D045744:Cell Line, Tumor; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008139:Loperamide / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000930:Antidiarrheals; D000970:Antineoplastic Agents; D002412:Cations; D011725:Pyridines; D013844:Thiazoles; D014665:Vasodilator Agents; D013629:Tamoxifen; D008139:Loperamide; C097880:MKT 077; D004110:Diltiazem