Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis.

Cancer Res
Authors
Keywords
Abstract

Aneuploidy, 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 -[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. .

Year of Publication
2017
Journal
Cancer Res
Volume
77
Issue
19
Pages
5272-5286
Date Published
2017 10 01
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-17-0049
PubMed ID
28775166
PubMed Central ID
PMC5772763
Links
Grant list
P30 CA014051 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States