University of Louisville

Poster Title

Candidate Drugs Target the APC/C to Induce Mitotic Arrest in Ovarian Cancer

Institution

University of Louisville

Abstract

Taxanes are a class of chemotherapeutic drug that disrupt microtubule function and cause mitotic arrest and cell death, however some cancer cells show resistance. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that acts as the master regulator of cell cycle progression. Inhibition of the APC/C should result in disruption of the cell cycle, resulting in arrest during mitosis and/or pseudo-G1. Previous in silico studies of the APC/C structure have yielded potential compounds that bind to the APC/C subunit ANAPC2. Three of these compounds (8, 10, 11) were tested on A2780/CP70 and SKOV3 ovarian carcinoma cells and tGM24 telomerase immortalized human fibroblasts. Cell morphology was observed during treatment with the compounds and showed signs of mitotic and apoptotic cells in a dose dependent manner. Mitotic index determinations revealed a significant mitotic delay in both cancer cells and fibroblasts treated with compounds 8, 10, and 11. Compounds 10 and 11 were more potent than compound 8 in inhibition of colony forming ability for all three cell lines. Fibroblasts showed some resistance to compound 8, however fibroblasts exposed to compound 11 showed complete inhibition of cell growth without characteristic morphological signs of apoptosis. All three compounds induced apoptosis in ovarian cancer cells, as indicated by increased caspase 3 activity, but not in fibroblasts. These results indicate that compounds targeting the APC/C can induce mitotic arrest and kill ovarian cancer cells while sparing normal cells. This research was supported by the University of Louisville Cancer Education Program NIH/NCI grant R25-CA134283.

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Candidate Drugs Target the APC/C to Induce Mitotic Arrest in Ovarian Cancer

Taxanes are a class of chemotherapeutic drug that disrupt microtubule function and cause mitotic arrest and cell death, however some cancer cells show resistance. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that acts as the master regulator of cell cycle progression. Inhibition of the APC/C should result in disruption of the cell cycle, resulting in arrest during mitosis and/or pseudo-G1. Previous in silico studies of the APC/C structure have yielded potential compounds that bind to the APC/C subunit ANAPC2. Three of these compounds (8, 10, 11) were tested on A2780/CP70 and SKOV3 ovarian carcinoma cells and tGM24 telomerase immortalized human fibroblasts. Cell morphology was observed during treatment with the compounds and showed signs of mitotic and apoptotic cells in a dose dependent manner. Mitotic index determinations revealed a significant mitotic delay in both cancer cells and fibroblasts treated with compounds 8, 10, and 11. Compounds 10 and 11 were more potent than compound 8 in inhibition of colony forming ability for all three cell lines. Fibroblasts showed some resistance to compound 8, however fibroblasts exposed to compound 11 showed complete inhibition of cell growth without characteristic morphological signs of apoptosis. All three compounds induced apoptosis in ovarian cancer cells, as indicated by increased caspase 3 activity, but not in fibroblasts. These results indicate that compounds targeting the APC/C can induce mitotic arrest and kill ovarian cancer cells while sparing normal cells. This research was supported by the University of Louisville Cancer Education Program NIH/NCI grant R25-CA134283.