A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxiso
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REVIEW
A novel plausible mechanism of NSAIDs‑induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator‑activated receptor Adam Kazberuk1 · Ilona Zareba1 · Jerzy Palka1 · Arkadiusz Surazynski1 Received: 1 April 2020 / Revised: 19 May 2020 / Accepted: 14 July 2020 © The Author(s) 2020
Abstract Although pharmaco-epidemiological studies provided evidence for the anticancer potential of non-steroidal anti-inflammatory drugs (NSAIDs), the mechanism of their anti-cancer activity is not known. Several lines of evidence suggest that proline dehydrogenase/proline oxidase (PRODH/POX) may represent a target for NSAIDs-dependent anti-cancer activity. PRODH/ POX catalyzes conversion of proline into Δ1-pyrroline-5-carboxylate releasing ATP or reactive oxygen species for autophagy/ apoptosis. Since NSAIDs are ligands of peroxisome proliferator-activated receptor (PPARs) and PPARs are implicated in PRODH/POX-dependent apoptosis we provided a hypothesis on the mechanism of NSAIDs-induced apoptosis in cancer cells. Keyword Cancer cells · Apoptosis · Non-steroidal anti-inflammatory drugs · Peroxisome proliferator-activated receptor · Proline dehydrogenase · Proline oxidase
Anticancer activity of NSAIDs Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs commonly prescribed due to their wide spectrum of pharmacological effects. However they are preferred for the treatment of inflammatory diseases. The molecular mechanism of NSAIDs action is related to the inhibition of cyclooxygenases (COX-1 and COX-2), enzymes catalyzing the biosynthesis of prostaglandins (PGs) from arachidonic and linoleic acids. COX-1 is expressed constitutively in most mammalian cells and maintains homeostasis of some physiological processes, while COX-2 is induced in response to inflammation [1]. While inhibition of COX-1
* Arkadiusz Surazynski [email protected] Adam Kazberuk [email protected] Ilona Zareba [email protected] Jerzy Palka [email protected] 1
Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15‑222 Białystok, Poland
evokes antiplatelet effect, inhibition of COX-2 has strong anti-inflammatory, antipyretic and analgesic effects [2, 3]. It is well established that inflammatory environment promotes cancer development. The mechanism of this process is due to increased levels of COX-2 and prostaglandin E2 (PGE2) [4–7] that promote proliferation, migration, invasion, and cell adhesion [8, 9]. According to these facts, medication with NSAIDs was associated with decreased risk of certain cancer types, particularly gastrointestinal tract cancers (gastric or colorectal cancer), lung, breast, and prostate cancers [10–14]. Clinical and pharmacoepidemiological studies provide evidence that aspirin and other cyclooxygenase-2 enzyme inhibitors lower recurrence of colorectal cancer by about 20% [12, 15, 16]. Another example is that regular, non-selective COX-2 NSAIDs treatment (i.e. aspirin and ibuprofen) caused a 69% reduction in the relative risk of lung cancer [1
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