L-Carnosine protects against Oxaliplatin-induced peripheral neuropathy in colorectal cancer patients: A perspective on targeting Nrf-2 and NF-κB pathways

Toxicol Appl Pharmacol. 2019 Feb 15;365:41-50. doi: 10.1016/j.taap.2018.12.015. Epub 2018 Dec 25.

Abstract

Background: Chemotherapy-induced peripheral neuropathy is a common side effect afflicting cancer patients treated with oxalipatin based chemotherapy.

Aim: The study investigated the potential prophylactic effect of L-carnosine against acute oxaliplatin neurotoxicity in colorectal cancer patients with emphasis on the redox (Nrf-2, MDA), inflammatory (NF-κB, TNF-α), and apoptotic (caspase-3) parameters.

Methods: In this pilot study, 65 patients were recruited using a prospective randomized controlled study design and enrolled randomly into two arms; Arm A, 31 patients received FOLFOX-6 regimen (oxaliplatin, 5FU & leucovorin) and Arm B, 34 patients received FOLFOX-6 regimen and daily oral L-carnosine (500 mg) along the treatment period. Patients were followed up for three months, then both arms were analyzed for neuropathy incidence/grade and any additional toxicities according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC version 4).

Results: The neuropathy grading evaluation of Arm B vs Arm A revealed that 17 patients (56.7%) vs 11 patients (35.5%) suffered grade 1, one patient (3.3%) vs 19 patients (61.3%) suffered grade 2, while 12 patients (40%) vs one patient (3.2%) were normal. In arm B, the addition of L-carnosine decreased significantly the levels/activity of NF-κB (27%) and TNF-α (36.6%); this anti-inflammatory effect entailed also its anti-oxidative and anti-apoptotic effects, thus MDA level (51.8%) and caspase-3 activity (49%) were also reduced, whereas Nrf-2 was increased (38.7%) as compared to Arm A. In both arms a significant correlation was only evident between TNF-α and the neuropathy grading score (P < .03); the correlation analysis was significantly positive between NF-κB and both Nrf-2 and caspase 3.

Conclusion: L-Carnosine exerted a neuroprotective effect against oxaliplatin-induced peripheral neuropathy in colorectal cancer patients by targeting Nrf-2 and NF-κB pathways.

Keywords: Caspase-3; L-carnosine; MDA; NF-κB; Nrf-2; Oxaliplatin; TNF-α.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Antioxidants / therapeutic use
  • Apoptosis / drug effects
  • Carnosine / adverse effects
  • Carnosine / therapeutic use*
  • Caspase 3 / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Egypt
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use
  • Humans
  • Leucovorin / adverse effects
  • Leucovorin / therapeutic use
  • Male
  • Malondialdehyde / metabolism
  • Middle Aged
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism*
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / therapeutic use*
  • Organoplatinum Compounds / adverse effects
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin / adverse effects
  • Oxaliplatin / therapeutic use*
  • Peripheral Nerves / drug effects*
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / pathology
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / pathology
  • Peripheral Nervous System Diseases / prevention & control*
  • Pilot Projects
  • Prospective Studies
  • Signal Transduction / drug effects
  • Time Factors
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • Neuroprotective Agents
  • Organoplatinum Compounds
  • Tumor Necrosis Factor-alpha
  • Oxaliplatin
  • Malondialdehyde
  • Carnosine
  • CASP3 protein, human
  • Caspase 3
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol