Abstract
The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days) increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) antagonist G3335 (30 µM) induced a similar peroxisomal impairment suggesting a relationship between PPARγ signaling and oxaliplatin neurotoxicity. The PPARγ agonist rosiglitazone (10 µM) reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg−1 per os) significantly reduced neuropathic pain evoked by noxious (Paw pressure test) and non-noxious (Cold plate test) stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role of peroxisomes in oxaliplatin-dependent nervous damage and suggest PPARγ stimulation as a candidate to counteract oxaliplatin neurotoxicity.
Highlights
Oxaliplatin is a chemotherapeutic compound widely used for treating colorectal cancer [1]
Primary rat astrocytes In astrocyte cell culture, peroxisomes were highlighted as catalase-positive organelles
After 48 h incubation, 10 mM oxaliplatin and 30 mM G3335 reduced the ratio by 26% and 49%
Summary
Oxaliplatin is a chemotherapeutic compound widely used for treating colorectal cancer [1]. Platinum-induced peripheral neuropathy is characterized by distal paresthesias and mild muscle contractions for at least 80% of oncologic patients after few hours to days from the first oxaliplatin infusion [2,3]. Oxaliplatin repeated treatment induces severe peripheral neuropathy that can affect approximately 50% of the patients receiving cumulative doses higher than 1000 mg/ m2 [4,5]. Anti-hyperalgesic compounds currently used to treat chemotherapy-induced pain, like antiepileptics or antidepressant, are weakly effective [6]. In a rat model of oxaliplatin-induced neuropathy we previously identified oxidative stress as a main biomolecular dysfunction showing a relationship between oxidative damage of the nervous system and pain [7]. Since oxaliplatin does not possess direct oxidative properties [8], redox unbalance seems due to a cellmediated effect able to alter the oxidative machinery
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