Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor pifithrin-μ

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. CIPN is the most frequent cause of dose reduction or treatment discontinuation in patients treated for cancer with commonly used drugs including taxanes and platinum-based compounds. No FDA-approved treatments for CIPN are available. In rodents, CIPN is represented by peripheral mechanical allodynia in association with retraction of intraepidermal nerve fibers (IENFs). The mechanism of chemotherapy-induced neurotoxicity is unclear but it has been established that mitochondrial dysfunction is an important component of the dysregulation in peripheral sensory neurons. We have shown earlier that inhibition of mitochondrial p53 accumulation with the small compound pifithrin-μ (PFT-μ) prevents cerebral neuronal death in a rodent model of hypoxic-ischemic brain damage. We now explore whether PFT-μ is capable of preventing neuronal mitochondrial damage and CIPN in mice. We demonstrate for the first time that PFT-μ prevents both paclitaxel- and cisplatin-induced mechanical allodynia. Electron microscopic analysis of peripheral sensory nerves revealed that PFT-μ secured mitochondrial integrity in paclitaxel-treated mice. In addition, PFT-μ administration protects against chemotherapy-induced loss of intra-epidermal nerve fibers (IENF) in the paw. To determine whether neuroprotective treatment with PFT-μ would interfere with the anti-tumor effects of chemotherapy, ovarian tumor cells were cultured in vitro with PFT-μ and paclitaxel. PFT-μ does not inhibit tumor cell death but even enhances paclitaxel-induced tumor cell death. These data are the first to identify PFT-μ as a potential therapeutic strategy for prevention of CIPN to combat one of the most devastating side effects of chemotherapy.

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

“…We therefore performed fixation and immunostaining of neuronal precursors in the subventricular zone (SVZ) and dentate gyrus (DG), as previously described [3]. In brief, mice were perfused with 4% paraformaldehyde (PFA).…”

“…Similar to methods we have previously described [3], synaptosomes were isolated and fixed in a solution containing 2% glutaraldehyde plus 2% PFA in PBS for at least 24 h. Samples were then fixed with a solution containing 3% glutaraldehyde plus 2% PFA in 0.1 M cacodylate buffer, pH 7.3, then washed in 0.1 M sodium cacodylate buffer and treated with 0.1% Millipore-filtered cacodylate-buffered tannic acid, post-fixed with 1% buffered osmium tetroxide for 30 min, and stained en bloc with 1% Millipore-filtered uranyl acetate. The samples were dehydrated in increasing concentrations of ethanol, infiltrated, and embedded in LX-112 medium.…”

“…However, in many cases cancer treatment is associated with severe neurotoxic side effects, including fatigue, peripheral pain [3], paresthesia, and cognitive deficits, that can persist long after completion of treatment [4]. These neurotoxicities not only disrupt social, educational, and occupational functioning, but also decrease survival by interfering with adherence to medication and health behavior.…”

“…In general, damaged mitochondria can give rise to increased oxidative stress, inflammation, and pro-apoptotic signaling [14]. We recently showed that co-administration of the small molecule pifithrin (PFT)-µ, an inhibitor of mitochondrial p53 accumulation, protects against taxane-induced and cisplatin-induced peripheral neuropathy[3]. In addition, we have demonstrated that PFT-µ is neuroprotective in a model of neonatal hypoxic–ischemic brain damage by preventing neuronal apoptosis [15].…”

Aqueous extract of Lithospermi radix attenuates oxaliplatin-induced neurotoxicity in both in vitro and in vivo models

“…It was reported that almost 50 % of cancer patients receiving a cumulative dose of oxaliplatin of 1,000 mg/m 2 or higher, which is the standard treatment protocol, experience OXIPN-related symptoms [10], 40 % of patients continue to experience neuropathy for six months or longer, and 13 % of patients discontinue chemotherapy due to neuropathy [14]. Unfortunately, however, the molecular mechanisms underlying development of CIPN including OXIPN have not been fully elucidated and no preventive or therapeutic agents for CIPN have been approved by the US FDA [15]. Therefore, only symptomatic managements are provided to CIPN patients in clinics [16].…”