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Activation of DNA damage response by antitumor therapy counteracts the activity of vinca alkaloids.

Anticancer Res. 33, 5273-5287 (2013)
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Background/Aim: Anthracyclines have been proven able to reduce the activity of vinca alkaloids by induction of cell-cycle arrest. The present study aims at identifying the critical initiation steps of signal transduction which transduce the inhibitory effects on the cytotoxicity of vinca alkaloids. MATERIALS AND METHODS: Several new cytostatic drug classes were evaluated together with vincristine in tumor cell lines and patients' tumor cells. RNA interference was used for molecular analyses. RESULTS: Inhibition of vincristine was observed by all cytostatic drugs, which induced cell-cycle arrest. Knockdown of proteins of the DNA damage response ascribed the inhibitory effect to a common pathway involving Chk-1, p53 and p21. Upstream of Chk-1 signal transduction depended on both ATM and ATR for all drugs except methotrexate. CONCLUSION: We have identified critical signaling steps of the DNA damage response system activated by cytostatic drugs, which reduce the anti-tumor activity of vinca alkaloids. The obtained results encourage the development of novel therapeutic strategies to prevent pathway interactions based on the molecular understanding of drug action and drug-drug interactions.  
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Publication type Article: Journal article
Document type Scientific Article
Keywords ATM; ATR; Chk1; DNA damage; cell-cycle arrest; p21; p53; vinca alkaloids; Cell-cycle Arrest; Cancer-therapy; Tumor-cells; P53; Checkpoints; Death; Anthracyclines; Proliferation; Mechanisms; Caspase-8
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