A synthetic resveratrol-curcumin hybrid derivative exhibits chemopreventive effects on colon pre-neoplastic lesions by targeting Wnt/β-catenin signaling, anti-inflammatory and antioxidant pathways

Abstract

Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-methoxyphenyl)-NE-((E)-4-methoxybenzylidene) acrylohydrazide (PQM-162), curcumin-resveratrol hybrid derivative, was designed by molecular hybridization using a hydrazone functionality as a spacer moiety between pharmacophoric fragments inspired by the parent compounds. Objectives: The present study aimed to evaluate the chemopreventive effects of the hybrid against pre-neoplastic lesions induced in the colon of rodents. Methods: The doses were determined based on the reduction in DNA damage induced by doxorubicin [15 mg/kg body weight (b.w.)] in peripheral blood of Swiss mice. Doses of 8, 16, 32, and 64 mg/kg b.w. were antimutagenic. For the evaluation of pre-neoplastic lesions in the colon, Wistar rats were treated with PQM-162 at doses of 0.5, 1, and 2 mg/kg b.w. for 6 weeks using three approaches: simultaneous treatment, pre-Treatment, and post-Treatment. Pre-neoplastic lesions were induced with 1,2 dimethylhydrazine (160 mg/kg b.w.). Key findings: PQM-162 reduced the formation of aberrant crypt foci in the simultaneous treatment and post-Treatment. TNF-α and COX-2 mRNA levels decreased, while Nrf2 mRNA levels increased. PQM-162 also reduced the expression of COX-2, PCNA, and β-catenin protein markers and increased Nrf2 expression. Conclusion: Our findings suggest a chemopreventive potential of PQM-162 in colorectal carcinogenesis, which acts on anti-inflammatory, antioxidant, and cell proliferation pathways.