Nearly more than a million cancer cases are being diagnosed worldwide annually, among which colorectal cancer is highly prevalent. Oxaliplatin (OXP) is a third generation platinum based anti-neoplastic agent mainly employed for colorectal cancer, marketed as FOLFOX- a combination drug of Oxaliplatin, 5-Fluorouracil and folinic acid. OXP acts by binding to the cancer cell DNA nucleus interrupting DNA replication and RNA transcription and finally inhibiting the neoplastic malignancy. Moreover, it also affects the normal cells leading to peripheral neuropathy and hence the clinical use is limited. About 50-90% of the patients receiving cumulative doses ⦣500mg/m₂ experiences peripheral neuropathy.
Oxaliplatin Induced Peripheral Neuropathy (OIPN) is characterized by acute and chronic symptoms; about 90% of patients after infusion experiences acute symptoms which include transient paraesthesia, dysthesia triggered or exacerbated by cold exposure. In contrast, long-term exposure produces sensory and motor dysfunction which could ultimately lead to the discontinuation of effective therapy. Currently approved remedies for peripheral neuropathy are limited as they provide only symptomatic relief.
Chemically OXP is a platinum atom bound by 1, 2-Diaminocyclohexane (DACH) and oxalate, which metabolizes to oxalate and dichloro(1,2-diaminocyclohexane)platinum. The exact pathomechanism underlying the OIPN is not clear yet, in-vitro studies delineated that acute neurotoxicity is involved in the alteration of Na˖-k˖ channel functioning by oxalate blocked. On the other hand accumulation of platinum adducts in DRG via the organic cation transporters viz.OCT1/2 is due to chronic neurotoxicity, which leads to damage of mitochondrial as well as nuclear DNA thereby neuronal dysfunction, alteration in redox potential, inhibition of neurite outgrowth and mitochondrial dysfunction.
Oxidative stress is one of the major underlying cause for mitochondrial dysfunction, inflammation and apoptosis which finally trigger neurodegeneration. OXP alters AMPK mediated PPARϒ pathway and inhibits mitophagy and mitochondrial biogenesis finally resulting in the cell death and thereby Peripheral neuropathy. It causes deficits in ETC chain leading to the accumulation of ROS and reduced anti-oxidant levels (GSH, SOD, GST, HO-1 etc…) via Nrf2. Hence, there is a therapeutic need to enhance anti-oxidant levels mediated by Nrf2 & mitochondrial biogenesis and prevent oxidative stress associated with mitochondrial dysfunction.
Umbelliferone (UMB) chemically a 7-hydroxycoumarin, a coumarin derivative of benzopyrone, occurs in many familiar plants of Umbelliferae family such as carrot, coriander and garden angelica, as well as plants from other families such as the mouse-ear hawkweed. It is a yellowish-white crystalline solid which has a slight solubility in hot water, but high solubility in ethanol. UMB has been reported to show anti-oxidant, anti-hyperglycemic, anti-neoplastic and anti-inflammatory activities. Reports have shown that it has a promising effect in attenuating anti-oxidant, PPARγ & Nrf2 levels. Hence this study is undertaken to evaluate the protective effect of UMB on Oxaliplatin Induced Peripheral Neuropathy (OIPN) mainly targeting Nrf2 and AMPK pathway.
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