Selective sensitivity to carboxyamidotriazole by human tumor cell lines with DNA mismatch repair deficiency.
We have previously reported that high-dose nifedipine had a selective antiproliferative effect on colon cancer cell lines deficient in DNA mismatch repair (MMR). We hypothesized that carboxyamidotriazole (CAI), a calcium channel blocker, would also have a selective inhibitory effect on colon cancer cell lines with DNA MMR deficiency. In addition, we speculated that this effect may also be seen in cell lines deficient in DNA MMR derived from other tumor types. Fourteen human cancer cell lines with and without DNA MMR derived from carcinomas of the colon, bladder, ovary and prostate were treated with CAI, vehicle or control drugs (nifedipine and 5-flurouracil). The effect of treatment on growth inhibition, invasion, apoptosis and cell cycle progression was assessed. Selective sensitivity to CAI was observed in all cancer cell lines deficient in MMR. Compared with the MMR-proficient cells, the matched deficient cells were significantly more sensitive to the growth inhibitory effect of CAI and nifedipine, but less sensitive to 5-flurouracil. CAI significantly inhibited the invasive ability of MMR-deficient cancer cells compared to 5-flurouracil. CAI induced more apoptosis but similar level of G(2)/M arrest in MMR (hMLH1- or hMSH6-)-deficient colon cancer cells than MMR-proficient counterparts. CAI selectively inhibits proliferation and invasion in MMR-deficient human cancer cell lines. The antitumor effect is at least partly explained by G2/M cell cycle arrest and induction of apoptosis. These findings may have clinical implications directing clinical trials in selectively targeted patients with DNA MMR tumors.
Yang
Jia-Lin
JL
Surgical Oncology Research Group, Oncology Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Qu
Xian-Jun
XJ
Department of Pharmacology, College of Pharmacy, Shandong University, Jinan, People's Republic of China.
Yu
Yan
Y
Orthopaedic Research Laboratory, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Kohn
Elise C
EC
Laboratory of Pathology, National Cancer Institute, National Institute of Health, Bethesda, MD.
Friedlander
Michael L
ML
Department of Medical Oncology, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales,Sydney, New South Wales, Australia.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D003124:Colorimetry / Q000379:methods; D053843:DNA Mismatch Repair / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009543:Nifedipine / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D014230:Triazoles; C062058:carboxyamido-triazole; D009543:Nifedipine; D005472:Fluorouracil