journal contribution posted on 2023-03-31, 00:43 authored by Yun-Chi Tang, Hui Yuwen, Kaiying Wang, Peter M. Bruno, Kevin Bullock, Amy Deik, Stefano Santaguida, Marianna Trakala, Sarah J. Pfau, Na Zhong, Tao Huang, Lan Wang, Clary B. Clish, Michael T. Hemann, Angelika Amon
Aneuploidy levels in Bub1b H/H and Cdc20 AAA/AAA MEFs.
National Key Research and Development Program of China
Strategic Priority Research Program of the Chinese Academy of Sciences
General Program of National Natural Science Foundation of China
National Thousand Talents
Ludwig Institute for Cancer Research
Howard Hughes Medical Institute
ARTICLE ABSTRACTAneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens. Cancer Res; 77(19); 5272–86. ©2017 AACR.