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Published in: Journal of Cancer Research and Clinical Oncology 8/2012

01-08-2012 | Original Paper

Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer

Authors: Johannes Meiler, Melanie Guyot, Sandra Hoffarth, Emmanuelle Wesarg, Yvonne Höhn, Frank Breitenbuecher, Martin Schuler

Published in: Journal of Cancer Research and Clinical Oncology | Issue 8/2012

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Abstract

Purpose

To investigate the combination of conventional cytotoxic anticancer agents and a small molecule kinase inhibitor in preclinical models of non-small-cell lung cancer (NSCLC).

Methods

We compared the induction of apoptosis by DNA-damaging anticancer drugs and PKC412, a predominantly protein kinase C (PKC)-specific small molecule inhibitor, in six NSCLC cell lines of different histologic and genetic backgrounds. The outcome of various combinations and schedules of DNA-damaging agents and PKC412 was studied, and isobolograms were calculated. Conditional expression of pro-apoptotic BAK was applied to specifically target apoptotic signal transduction in combination with drug therapy.

Results

Resistance of NSCLC cells to DNA damage–induced apoptosis was mainly determined at the mitochondrial step of the intrinsic pathway of caspase activation. PKC412 effectively inhibited the growth factor signal transduction, but failed to induce apoptosis in NSCLC cells resistant to DNA-damaging agents. Combining conventional anticancer drugs with PKC412 at different doses and schedules resulted in unpredictable outcomes, including synergistic, additive, and antagonistic interactions. In contrast, conditional expression of BAK reliably sensitized drug-resistant NSCLC cells to apoptosis induced by cytotoxic agents or PKC412.

Conclusions

Combining DNA-damaging anticancer drugs with a pharmacologic inhibitor of growth and survival factor signaling in NSCLC may result in unpredictable treatment outcomes. In contrast, targeting specific death effector mechanisms, such as apoptotic signal transduction, is a promising strategy to sensitize NSCLC to cytotoxic agents or kinase inhibitors.
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Metadata
Title
Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer
Authors
Johannes Meiler
Melanie Guyot
Sandra Hoffarth
Emmanuelle Wesarg
Yvonne Höhn
Frank Breitenbuecher
Martin Schuler
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 8/2012
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-012-1220-4

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