Emergence of chemoresistance is the major cause of death in patients with cancer. To discover compounds that might reverse chemoresistance, we undertook a compound screen to identify molecules that would convert a resistance cell into one that is sensitive. We performed this screen in WTK1, a lymphoblastoid cell line with mutant p53 known to be resistant to chemotherapy. We conducted a high-throughput screen using 83,745 small molecules in the presence or absence of daunorubicin at an IC25 to identify novel compounds that prime cells for chemotherapy-induced apoptosis. We identified C3 as a “hit,” defined as a compound that did not significantly alter viability of cells alone, but significantly increased daunorubicin-induced cell death. We confirmed the effects C3 in a variety of cell types including leukemia, colon, neuroblastoma, breast and ovarian. To determine whether this effect was specific to daunorubicin, we assessed C3's ability to synergize with a wide variety of other genotoxic agents and found that it was highly synergistic with platinating agents. Because cisplatin resistance is the major obstacle in ovarian cancer treatment, we used ovarian cancer lines in our mechanistic studies. We found that C3 synergizes with cisplatin and daunorubicin in a caspase-3 dependent manner, but the mechanism by which C3 primes cells for death did not involve mismatch repair or mitochondrial membrane permeability. Because cisplatin and daunorubicin induce cell cycle arrest, we hypothesized that C3 might alter the regulation of progression of the cell cycle. We found that while cisplatin and daunorubicin have arrested cell cycle profiles on their own, the profiles appear normal when combined with C3 before the cells die. These observations suggest a novel mechanism in which C3 induces apoptosis by forcing cells with damaged genomes through the cell cycle, resulting in apoptosis.

Citation Format: Kathryn Elizabeth Wolak, Kenan Onel. C3: A small molecule that reverses chemoresistance by inhibition of cell cycle arrest. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3768. doi:10.1158/1538-7445.AM2014-3768

©2014 American Association for Cancer Research.
2014