Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.
N,N-diethyl-2-[4-(phenylmethyl)phenoxyl]ethanamine (tesmilifene), a tamoxifen derivative with antihistamine activity, greatly enhanced the survival of doxorubicin-treated, advanced stage breast cancer patients in a phase III trial. However, the molecular basis of tesmilifene action is not firmly established. The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma (HNSCC) and breast carcinoma cell lines as a model system. Multidrug resistant (MDR) variants of an HNSCC cell line, HN-5a/V15e, and a breast carcinoma cell line, MCF-7/V25a, both highly overexpressed mdr1 (ABCB1) mRNA and the proteins P-glycoprotein and glutathione transferase-pi. Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect. Tesmilifene had minimal effect on drug cytotoxicity against the parental cell lines. However, the same tesmilifene treatment enhanced cytotoxicity of docetaxel, paclitaxel, epirubicin, doxorubicin, and vinorelbine against both MDR cell lines by up to 50%. Flow cytometric measurement of annexin V/propidium iodide staining demonstrated that tesmilifene increased the killing of HN-5a/V15e cells caused by docetaxel after 24 and 48h exposure. Tesmilifene increased accumulation of radiolabelled vincristine in HN-5a/V15e cells, over 4h, by up to 100%. The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs. The mechanism of enhancement appears to be related to expression of an ABC pump-dependent, MDR phenotype.
Ferguson
Peter J
PJ
Lawson Health Research Institute, London Health Sciences Centre, 790 Commissioners Road, London, Ontario, Canada. peter.ferguson@uwo.ca
Brisson
Alayne R
AR
Koropatnick
James
J
Vincent
Mark D
MD
D017209:Apoptosis; D001483:Base Sequence; D001688:Biological Products / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D019450:Genes, MDR; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D010647:Phenyl Ethers / Q000494:pharmacology*
D001688:Biological Products; D017931:DNA Primers; D006633:Histamine Antagonists; D010647:Phenyl Ethers; C043062:tesmilifene