PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol

Arpad Szanto, Eva E. Hellebrand, Zita Bognar, Zsuzsanna Tucsek, Aliz Szabo, Ferenc Gallyas, Balazs Sumegi, Gabor Varbiro

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

PARP inhibitors combined with DNA-damage inducing cytostatic agents can lead to effective tumor therapy. However, inhibition of poly(ADP-ribose) polymerase (PARP-1; EC 2.4.2.30) induces the activation of PI-3-kinase-Akt pathway, which can counteract the effectiveness of this therapy. To understand the role of Akt activation in the combined use of cytostatic agent and PARP inhibition, we used taxol (paclitaxel) as an antineoplastic agent, which targets microtubules and up-regulates mitochondrial ROS production, together with (i) pharmacological inhibition (PJ-34), (ii) siRNA knock-down and (iii) transdominant expression of the DNA binding domain of PARP-1. In all cases, PARP-1 inhibition leads to suppressed poly-ADP-ribosylation of nuclear proteins, prevention of NAD+ depletion and significant resistance against taxol induced caspase-3 activation and apoptotic cell death. Paclitaxel induced a moderate increase in Akt activation, which was significantly augmented by PARP inhibition, suggesting that PARP inhibition-induced Akt activation could be responsible for the cytostatic resistance. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance. Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinase-Akt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.

Original languageEnglish
Pages (from-to)1348-1357
Number of pages10
JournalBiochemical Pharmacology
Volume77
Issue number8
DOIs
Publication statusPublished - Apr 15 2009

Fingerprint

Cytostatic Agents
Paclitaxel
Phosphatidylinositol 3-Kinases
Chemical activation
Cell Death
Cell death
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Tumors
DNA
Nuclear Proteins
Drug Resistance
Microtubules
Caspase 3
DNA Repair
Antineoplastic Agents
NAD
Adenosine Diphosphate
Small Interfering RNA
DNA Damage
Neoplasms

Keywords

  • Akt activation
  • Antitumor treatment
  • PARP inhibition
  • PI-3 kinase
  • Taxol resistance

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol. / Szanto, Arpad; Hellebrand, Eva E.; Bognar, Zita; Tucsek, Zsuzsanna; Szabo, Aliz; Gallyas, Ferenc; Sumegi, Balazs; Varbiro, Gabor.

In: Biochemical Pharmacology, Vol. 77, No. 8, 15.04.2009, p. 1348-1357.

Research output: Contribution to journalArticle

Szanto, Arpad ; Hellebrand, Eva E. ; Bognar, Zita ; Tucsek, Zsuzsanna ; Szabo, Aliz ; Gallyas, Ferenc ; Sumegi, Balazs ; Varbiro, Gabor. / PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol. In: Biochemical Pharmacology. 2009 ; Vol. 77, No. 8. pp. 1348-1357.
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