Oxaliplatin Neurotoxicity Involves Peroxisome Alterations. PPARγ Agonism as Preventive Pharmacological Approach

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.

Effect of the SOD mimetic MnL4 on in vitro and in vivo oxaliplatin toxicity: Possible aid in chemotherapy induced neuropathy

“…In our research, we have already characterized ROS as central players of oxaliplatin CIN using in vitro and in vivo models [4,20,35]. The results herein presented show that the SOD mimetic poliaminopolicarboxylic compound MnL4 prevents cellular damage induced by oxaliplatin in vitro, reducing oxidative stress and normalizing calcium dynamic in isolated astrocytes pre-treated with the anticancer drug.…”

Proliferation and fission of peroxisomes — An update

“…Indeed, catalase induction by PPARγ may be independent of the process of peroxisome proliferation in individual cell types. Zanardelli and colleagues reported that astrocytes respond with an increase in peroxisome proliferation induced by the PPARγ antagonist G3335 but in parallel decreased catalase expression, whereas rosiglitazone as a PPARγ agonist, did not increase peroxisome abundance but induced catalase expression [191]. This implies that the peroxisome proliferation reported after G3335 administration is a compensatory response to antagonize the specific reduction in catalase levels caused by the inhibition of PPARγ.…”

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…oxaliplatin dosing and clinically relevant levels of oxaliplatin (as inorganic platinum) in plasma (Zanardelli et al. 2014). …”