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

Abstract:

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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

Ehrhardt H,Pfeiffer S,Schrembs D,Wachter F,Grunert M,Jeremias I

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

5273-87

issue

12

eissn

0250-7005

issn

1791-7530

pii

33/12/5273

journal_volume

33

pub_type

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