Activation of DNA Damage Response by Antitumor Therapy Counteracts the Activity of Vinca Alkaloids

作者：Ehrhardt Harald^*; Pfeiffer Sarah; Schrembs David; Wachter Franziska; Grunert Michaela; Jeremias Irmela

来源：Anticancer Research, 2013, 33(12): 5273-5287.

• ATM
• ATR
• Chk1
• p53
• p21
• cell-cycle arrest
• vinca alkaloids
• DNA damage

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.

• 出版日期2013-12