ReviewPARP inhibition in platinum-based chemotherapy: Chemopotentiation and neuroprotection
Graphical abstract
Introduction
Cancer is a major health burden and a leading cause of mortality worldwide [1,2]. With an estimated 14.1 million new cancer cases occurring worldwide in 2012, and over 20 million new cancer cases expected annually as early as 2025 [3], cancer represents an ever-increasing affliction [4].
Chemotherapy is a pillar of current cancer treatment. Since their discovery in the 1960’s, platinum chemotherapeutics in particular have played a pivotal role in the treatment of a broad range of malignancies including head and neck, lung, colorectal, ovarian, breast and genitourinary cancer [5]. Following the finding that cis-diamminedichloro-platinum (III) (cisplatin) inhibited cell division of Escherichia coli (E.coli) [6], several platinum-based compounds structurally similar to cisplatin including carboplatin and oxaliplatin, were approved for cancer treatment [5]. Though these compounds have marked differences in their therapeutic use and pharmacokinetics, severe neurotoxicity is conserved across all platinum chemotherapeutics [7]. Toxicity to the peripheral nervous system is a major dose-limiting factor affecting up to 60% of platinum chemotherapy-treated patients [7]. Commonly presenting as paraesthesia and dysaesthesia in the fingers and toes in the early stages of treatment, symptoms of chemotherapy-induced peripheral neuropathy often spread proximally to affect both lower and upper extremities in a characteristic ‘stocking and glove’ distribution [8]. Symptoms can be extremely painful and debilitating, reducing functional ability and hindering quality of life. Alongside this peripheral neuropathy, platinum-based agents are linked to a high incidence of gastrointestinal side-effects, with some studies reporting that up to 90% of patients experience vomiting, nausea, diarrhoea and/or constipation during and long after chemotherapy [9]. It is widely believed that chemotherapy-induced gastrointestinal dysfunction revolves mainly around mucosal damage and ulceration, however, increasing evidence suggests that enteric neuropathy may be a contributing factor [[10], [11], [12], [13], [14], [15]]. Gastrointestinal side-effects of platinum-based chemotherapeutics are of particular clinical concern contributing to dose-reductions, dose delays, and cessation of treatment which significantly compromises treatment outcomes.
Utilization of antioxidants, reactive oxygen species (ROS) scavengers, and PARP inhibitors to reduce side-effects in animal models of chemotherapy-induced sensory peripheral neuropathy and gastrointestinal dysfunction has yielded promising results [[16], [17], [18], [19]].
Section snippets
Platinum chemotherapeutics and peripheral neuropathy
The discovery and development of new platinum-containing drugs have been an integral part of anti-cancer drug advancement over the last several decades. The serendipitous discovery that cisplatin inhibited cell division in the early 1960’s [6] prompted the re-evaluation of thousands of biologically active platinum complexes as potential chemotherapeutic agents [20]. As a result, platinum-based chemotherapeutics are a large cohort of anti-cancer compounds used to treat a broad range of malignant
Platinum chemotherapy-induced enteric neuropathy and gastrointestinal dysfunction
Alteration of the enteric nervous system has been implicated in gastrointestinal dysfunction associated with several disorders including achalasia, Hirschsprung’s disease, intestinal neuronal dysplasia, Chagas disease, irritable bowel syndrome, inflammatory bowel disease and severe idiopathic slow transit constipation [[57], [58], [59], [60], [61], [62], [63], [64]].
Subtle changes to the enteric nervous system, not evident in conventional histological examination, have been suggested underlying
Oxidative stress associated with platinum-induced neuropathy
Oxidative stress arises when the generation of ROS exceeds the capacity of cellular antioxidant systems to remove it, resulting in redox imbalance and heightened free-radical production [81]. In homeostatic circumstances, regulated oxidative stress signals can initiate diverse cellular responses involved in protection, mitochondrial fission and fusion, and autophagy of abnormal mitochondria and cells in an attempt to protect neighbouring mitochondria and cells [82]. Conversely, unregulated and
Mitochondrial damage
ROS can cause several types of DNA damage, including DNA single and double strand breaks and nucleotide base modifications. Therefore, efficient repair of ROS-induced DNA damage is important for preventing mutations and maintaining the stability of the mitochondrial genome [101]. mtDNA in particular is prone to oxidative damage compared with its nuclear counterpart, which may be due to its location close to endogenously generated ROS [102], and to the fact that mtDNA lacks introns and undergoes
PARP inhibitors as chemotherapeutics and chemopotentiators
Poly(ADP-ribosyl)-ation has been implicated in the regulation of a diverse array of cellular processes ranging from DNA repair, chromatin organization, transcription, replication to protein degradation [117]. Poly(ADP-ribose) polymerase-1 (PARP1) specifically is heavily involved in BER and non-homologous end joining pathways that facilitate DNA repair of both single and double strand breaks [118]. Activated PARP1 cleaves NAD + into nicotinamide and ADP-ribose, which is polymerized and
PARP inhibition as a neuroprotective treatment
PARP over-activation resulting in cellular NAD + exhaustion and subsequent ATP depletion has been shown to contribute to tissue injury in diabetes, myocardial or cerebral ischemia reperfusion and inflammation [117] (Fig. 2). In particular, PARP over-expression has been linked to a plethora of neurodegenerative and neuropathic disorders including Parkinson’s disease, Alzheimer’s disease, diabetic neuropathy and chemotherapy-induced peripheral neuropathy [17,[131], [132], [133], [134], [135]].
PARP inhibition as a treatment for chemotherapy-induced gut dysfunction
Growing research supports the notion of enteric neuroprotection as a therapeutic target for gastrointestinal dysfunction in a variety of conditions. The novel cytoprotectant, BGP-15, is a pharmacological modulator of the cellular response to stress, acting as a PARP1 inhibitor, heat shock protein (HSP) co-inducer [144,145], and a mild anti-oxidant [146] in a variety of tissues. Clinical application of BGP-15 has been investigated in a wide variety of pathological conditions and has demonstrated
Conclusion
Although platinum chemotherapeutics represent the backbone of anti-cancer therapy for several malignancies, their efficacy is often overshadowed by a vast array of side-effects. Optimization of platinum chemotherapeutic agents to ameliorate dose-limiting side-effects such as constipation and diarrhoea is essential to improve the prognostic outcome of many cancers. PARP inhibitors have demonstrated promising chemopotentiating effects when administered in combination with platinum
Conflict of interests
The authors declare they have no competing interests.
Acknowledgments
This study was supported by Victoria University (Australia) Research Development Grant. RMM is supported by the College of Health and Biomedicine, Victoria University, Australia.
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