Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating major side effect of cancer treatment, is characterized by pain and sensory loss in hand and feet. Platinum-based chemotherapeutics like cisplatin frequently induce CIPN. The molecular mechanism underlying these neurotoxic symptoms is incompletely understood and there are no preventive or curative interventions. We hypothesized that cisplatin acts as a cellular stressor that triggers p53 accumulation at mitochondria, leading to mitochondrial dysfunction and CIPN. To test this hypothesis, we examined the effect of the small molecule pifithrin-μ (PFT-μ), an inhibitor of p53 mitochondrial association on CIPN and the associated mitochondrial dysfunction. We show here for the first time that in vivo cisplatin rapidly increases mitochondrial accumulation of p53 in dorsal root ganglia (DRG), spinal cord, and peripheral nerve without evidence for apoptosis. Cisplatin-treatment also reduced mitochondrial membrane potential and lead to abnormal mitochondrial morphology and impaired mitochondrial function in DRG neurons. Pre-treatment with PFT-μ prevented the early cisplatin-induced increase in mitochondrial p53 and the reduction in mitochondrial membrane potential. Inhibition of the early mitochondrial p53 accumulation by PFT-μ also prevented the abnormalities in mitochondrial morphology and mitochondrial bioenergetics (reduced oxygen consumption rate, maximum respiratory capacity, and adenosine triphosphate synthesis) that develop in DRG and peripheral nerve after cisplatin-treatment. Functionally, inhibition of mitochondrial p53 accumulation prevented the hallmarks of CIPN including mechanical allodynia, peripheral sensory loss (numbness) as quantified by an adhesive-removal task, and loss of intra-epidermal nerve fibers. In conclusion, PFT-μ is a potential neuroprotective agent that prevents cisplatin-induced mitochondrial dysfunction in DRG and peripheral nerves thereby protecting against CIPN through blockade of the early cisplatin-induced increase in mitochondrial p53. Notably, there is accumulating evidence that PFT-μ has anti-tumor activities and could therefore be an attractive candidate to prevent CIPN while promoting tumor cell death.

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

“…Recent studies have indicated that chemotherapeutic agents trigger a similar damage pathway. For example, we demonstrated that cisplatin treatment rapidly increases mitochondrial levels of p53 in DRG neurons, followed by a reduction in mitochondrial membrane potential and ultimately by the disruption of mitochondrial integrity and function . It is interesting to note that we found that the mitochondrial protectant pifithrin‐μ, which prevents mitochondrial accumulation of p53, also prevented paclitaxel‐induced and cisplatin‐induced neuropathic pain and sensory loss and averted the loss of IENFs in mouse models of CIPN .…”

“…Consistent with the mitotoxicity theory of CIPN, swollen and vacuolated mitochondria appear in peripheral nerves and dorsal root ganglion (DRG) neuronal cell bodies in rodent models of peripheral neuropathy induced by paclitaxel, cisplatin, oxaliplatin, bortezomib, or vincristine . These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN . More specifically, impairments in mitochondrial basal respiration, maximal respiration capacity, and ATP production are observed …”

“…It is interesting to note that we found that the mitochondrial protectant pifithrin‐μ, which prevents mitochondrial accumulation of p53, also prevented paclitaxel‐induced and cisplatin‐induced neuropathic pain and sensory loss and averted the loss of IENFs in mouse models of CIPN . Pifithrin‐μ not only prevented CIPN symptoms but also protected against loss of mitochondrial membrane potential, abnormalities in mitochondrial morphology, and functional mitochondrial deficiencies in DRG neurons . It is important to note that because pifithrin‐μ targets the p53‐mitochondrial pathway without affecting the transcriptional functions of p53, it does not negatively affect the tumor‐killing effects of chemotherapy .…”

“…Persistent mitochondrial dysfunction generates nitro‐oxidative stress (described below), which causes nitro‐oxidative damage to mitochondrial DNA and proteins, further aggravating mitochondrial damage and leading to energy deficiency in sensory neurons . Consistent with the mitotoxicity theory of CIPN, swollen and vacuolated mitochondria appear in peripheral nerves and dorsal root ganglion (DRG) neuronal cell bodies in rodent models of peripheral neuropathy induced by paclitaxel, cisplatin, oxaliplatin, bortezomib, or vincristine . These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN .…”

“…These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN . More specifically, impairments in mitochondrial basal respiration, maximal respiration capacity, and ATP production are observed …”