Premium
Glucosylceramide synthase inhibition enhances vincristine‐induced cytotoxicity
Author(s) -
Olshefski Randal S.,
Ladisch Stephan
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1301
Subject(s) - ceramide , cytotoxicity , vincristine , apoptosis , programmed cell death , sphingolipid , biochemistry , biology , cell growth , ceramide synthase , pharmacology , cancer research , chemistry , microbiology and biotechnology , in vitro , chemotherapy , genetics , cyclophosphamide
As a strategy to enhance tumor cell sensitivity to vincristine, we tested whether modulation of sphingolipid metabolism would alter vincristine cytotoxicity since this is linked to accumulation of the intermediate metabolite, ceramide. We blocked ceramide metabolism in a series of variably vincristine‐resistant cell lines derived from CCRF‐CEM leukemia cells using an inhibitor of glucosylceramide synthase, DL ‐ threo ‐phenyl‐2‐hexadecanoylamino‐3‐pyrrolidino‐1‐propanol (PPPP). PPPP alone (1.0 μM), while nearly completely blocking glucosylceramide synthesis, was not toxic and did not increase cellular ceramide levels. Vincristine alone was toxic, caused apoptosis or programmed cell death (PCD) and caused an elevation in ceramide levels. Strikingly, the combination of PPPP and vincristine resulted in a further increase, over that of vincristine alone, of (i) cellular ceramide concentration, (ii) cytotoxicity associated with PCD and (iii) G 2 /M cell‐cycle arrest. PPPP had no effect on P‐glycoprotein expression or function. We conclude that vincristine cytotoxicity occurs in part through a ceramide‐dependent mechanism, resulting in both G 2 /M block as well as PCD, and that the blockade of glucosylceramide synthase, in itself not toxic, causes augmented accumulation of ceramide resulting from vincristine exposure, which in turn maximizes ceramide‐dependent, vincristine‐induced cytotoxicity. Inhibition of glucosylceramide synthesis may be a means of circumventing drug resistance by enhancing signaling through a cell‐death pathway. © 2001 Wiley‐Liss, Inc.