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Cancer Chemotherapy and Pharmacology

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01-02-2008 | Original Article

Cell death in response to antimetabolites directed at thymidylate synthase

Authors: Karen W. Barbour, Franklin G. Berger

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2008

Abstract

Purpose

Thymidylate synthase (TS) is an indispensable enzyme in the de novo biosynthesis of TMP during DNA replication and cell growth, and has, therefore, been an important target for several classes of antimetabolites used in cancer chemotherapy. While most investigations of the action of TS-directed agents have focused on apoptosis as the primary means of cell death, little is known regarding the role, if any, of non-apoptotic mechanisms. In the present study, we have examined the mode of cell death induced by several TS inhibitors.

Methods

Apoptosis and necrosis in response to TS inhibitors was assessed. The roles of caspases and the transcriptional regulator nuclear factor kappa B (NFκB) in drug-induced cell death were analyzed. Finally, drug-mediated changes in expression of several proteins involved in regulation of apoptosis were analyzed.

Results

Though human colon tumor cells exposed to TS inhibitors undergo classical apoptosis, it is not the predominant mechanism of response; rather, a necrosis-like mechanism prevails. The apoptotic response to TS inhibitors is caspase-dependent, and is promoted by NFκB. In contrast, the necrosis-like response is independent of both caspases and NFκB. Exposure to TS inhibitors induces PARP cleavage, but does not alter expression of the pro or activated forms of caspases-3 or caspases-8, Fas, or FasL. Treatment with the death-inducing cytokine TNFα, like TS inhibitors, results in a limited extent of apoptosis that is both caspase- and NFκB-dependent; however, unlike TS inhibitors, the cytokine does not induce necrosis.

Conclusion

Classical apoptosis occurs to a limited extent in human colon tumor cells exposed to TS inhibitors, with caspase-independent necrosis being the prinicipal mechanism of cell death. We suggest that the role of necrosis and necrosis-like mechanisms should be considered in future studies of the action of TS-directed antimetabolites, as well as other chemotherapeutic agents.

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Title: Cell death in response to antimetabolites directed at thymidylate synthase
Authors: Karen W. Barbour
Franklin G. Berger
Publication date: 01-02-2008
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0461-4

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Abstract

Purpose

Methods

Results

Conclusion

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