TY - JOUR
T1 - Inhibition of mitochondrial p53 accumulation by PFT-µ prevents cisplatin-induced peripheral neuropathy
AU - Maj, Magdalena A.
AU - Ma, Jiacheng
AU - Krukowski, Karen N.
AU - Kavelaars, Annemieke
AU - Heijnen, Cobi J.
N1 - Publisher Copyright:
© 2017 Maj, Ma, Krukowski, Kavelaars and Heijnen.
PY - 2017/4/18
Y1 - 2017/4/18
N2 - 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 mechanismunderlying 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 CIPNincluding 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 CIPNthrough 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 CIPNwhile promoting tumor cell death.
AB - 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 mechanismunderlying 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 CIPNincluding 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 CIPNthrough 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 CIPNwhile promoting tumor cell death.
KW - Bioenergetics
KW - Cisplatin
KW - Mitochondria
KW - Peripheral neuropathy
KW - Pifithrin-µ
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=85018896263&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018896263&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2017.00108
DO - 10.3389/fnmol.2017.00108
M3 - Article
C2 - 28458631
AN - SCOPUS:85018896263
SN - 1662-5099
VL - 10
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 108
ER -