Selective sensitivity to carboxyamidotriazole by human tumor cell lines with DNA mismatch repair deficiency

Abstract

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 (hMLH12 or hMSH62)-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.

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

“…In other words, our finding raises the possibility that patients who initially respond to the frontline therapy in use today may evolve not only treatment resistance, but also an MMR-defective hypermutator phenotype. If such a mechanism indeed underlies emergence of MMR-defective resistance, one may speculate that selective strategies targeting mismatch-repair deficiency 50 would represent a rational upfront combination that may prevent or minimize emergence of such resistance. Validation of this hypothesis will have immediate clinical impact and implication for therapeutic design.…”

Targeting the DNA Damage Response in Cancer

“…However, agents inducing DNA interstrand cross-links or inhibiting DNA synthesis preferentially kill tumor cells with defective MMR. Furthermore, gemcitabine preferentially radiosensitizes MMR-defective cancer cells, and MMR-deficiency leads to hypersensitivity to carboxyamidotriazole (CAI) . Thus, by confirming the MSI phenotype of the tumor or by locating hypoxic regions of tumors, treatments that selectively target either MMR-proficient or MMR-deficient cells should be considered to improve therapy.…”

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas

“…34 Tissue obtained after chemoradiotherapy and before study enrollment was not available in most cohort 1 patients; therefore, it is not possible to determine if the hypermutation status preceded study entry. At least one patient displayed a hypermutator phenotype before enrollment, and cell lines from a variety of tumors displaying mismatch-repair deficiencies have been shown to be selectively sensitive to calcium blockade, 38 which could potentially explain the high frequency of hypermutators among responders. However, at least one patient developed a hypermutator phenotype in cohort 2 after exposure to CTO and TMZ, and a more plausible explanation may be that the hypermutation status developed as a consequence of prolonged TMZ exposure in patients treated successfully.…”