Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.
Highlights
Inhibitors of the constitutive mammalian enzyme poly(ADP-ribose) polymerase (PARP)1 received renewed interest in recent years due to their importance in cancer therapy [1]
Accumulating clinical evidence indicates that PARP inhibitors can be successfully applied in cancers not responding to conventional treatments
At the same time, ongoing clinical trials combining PARP inhibitors with agents targeting non-homologous recombination DNA repair systems, signaling pathways, angiogenesis, or immune checkpoint mechanisms intend to extend the therapeutic potential of PARP inhibitors well beyond their present one
Summary
Inhibitors of the constitutive mammalian enzyme poly(ADP-ribose) polymerase (PARP) received renewed interest in recent years due to their importance in cancer therapy [1]. Their use is based on the synthetic lethality theory [2], i.e., to block the single-strand DNA break repair process in double-strand DNA break repair (BRCA1/2) deficient cancer cells that selectively eliminates the cancer cells via DNA damage accumulation while not affecting normal cells possessing intact double-strand. Review articles focusing on the role of PARP inhibitors in DNA repair vastly dominate over those that at least mention the effect of PARP inhibition on kinase signaling, the latter effect is an important limiting factor in the cancer therapy [5], and a pivotal mechanism in non-cancerous therapeutic applications of the PARP inhibitors [6]. We discuss the role of the PARP-Akt interplay in non-oncological disease conditions and their experimental models
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