Abstract
Oxaliplatin (Oxa) treatment to SH-SY5Y human neuroblastoma cells has been shown by previous studies to induce oxidative stress, which in turn modulates intracellular signaling cascades resulting in cell death. While this phenomenon of Oxa-induced neurotoxicity is known, the underlying mechanisms involved in this cell death cascade must be clarified. Moreover, there is still little known regarding the roles of neuronal mitochondria and cytosolic compartments in mediating Oxa-induced neurotoxicity. With a better grasp of the mechanisms driving neurotoxicity in Oxa-treated SH-SY5Y cells, we can then identify certain pathways to target in protecting against neurotoxic cell damage. Therefore, the purpose of this study was to determine whether one such agent, melatonin (Mel), could confer protection against Oxa-induced neurotoxicity in SH-SY5Y cells. Results from the present study found Oxa to significantly reduce SH-SY5Y cell viability in a dose-dependent manner. Alternatively, we found Mel pre-treatment to SH-SY5Y cells to attenuate Oxa-induced toxicity, resulting in a markedly increased cell viability. Mel exerted its protective effects by regulating reactive oxygen species (ROS) production and reducing superoxide radicals inside Oxa-exposed. In addition, we observed pre-treatment with Mel to rescue Oxa-treated cells by protecting mitochondria. As Oxa-treatment alone decreases mitochondrial membrane potential (Δψm), resulting in an altered Bcl-2/Bax ratio and release of sequestered cytochrome c, so Mel was shown to inhibit these pathways. Mel was also found to inhibit proteolytic activation of caspase 3, inactivation of Poly (ADP Ribose) polymerase, and DNA damage, thereby allowing SH-SY5Y cells to resist apoptotic cell death. Collectively, our results suggest a role for melatonin in reducing Oxa induced neurotoxicity. Further studies exploring melatonin’s protective effects may prove successful in eliciting pathways to further alter the neurotoxic pathways of platinum compounds in cancer treatment.
Highlights
Neurotoxicity is one major side effect seen in platinum-based chemotherapy that counteracts the administration of an effective dose and regularly prompts patients to withdraw treatment
Bright field images clearly demonstrated Oxa-exposed SH-SY5Y cells to display morphological alterations typically linked to an episode of apoptotic cell death
Results from the present study clearly suggested that Oxaliplatin (Oxa), a platinum-based anti-neoplastic agent, exerts cytotoxic effects to SH-SY5Y human neuroblastoma cells in a dose-dependent manner
Summary
Neurotoxicity is one major side effect seen in platinum-based chemotherapy that counteracts the administration of an effective dose and regularly prompts patients to withdraw treatment. Platinum derivatives are among the most frequently utilized anticancer agents. One such drug, Oxaliplatin (Oxa), has been shown to cause higher cytotoxicity and produce less DNA adducts compared to CP (cisplatin) at equimolar concentrations [1]. Neurotoxicity in the setting of acute exposures may emerge following the first dose Symptoms such as cold-provoked paresthesias and withdrawal cramps may appear within 1 week of the last administered dose. It is possible for chronic, painful symptoms to develop and reappear sporadically in the months following treatment discontinuation, namely as a result of lingering Oxa-accumulation in the body. The possible causes of Oxa induced neurotoxicity (both acute and chronic) are still not completely understood
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