Chemopreventive Effects of Boldine and Naringenin on DMH-Induced Colorectal Carcinogenesis.

Abstract

Introduction: Colorectal cancer causes high global mortality. Natural compounds boldine and naringenin exhibit preventive potential by reducing oxidative stress, inhibiting cell proliferation, and regulating inflammation, making them promising, safer therapeutic agents. This study evaluated the chemopreventive potential of boldine and naringenin using DMH-induced Wistar rats, in silico EGFR binding studies, and in vitro antiproliferative assays.

Methods: A multi-pronged approach was employed to evaluate the chemopreventive potential of boldine and naringenin. In silico molecular docking and dynamics simulations assessed binding affinity and stability with EGFR kinase, a key regulator of cancer progression. In vitro studies evaluated cytotoxicity in HCT116 colorectal cancer (CRC) cells using the MTT assay, and antioxidant activity was measured using the DPPH assay. In vivo, Wistar rats were divided into five groups: Control, DMH only, DMH + Boldine, DMH + Naringenin, and DMH + Vincristine. Lipid profiles, oxidative stress markers, and colon histopathology were analyzed.

Results: Molecular docking revealed boldine's stronger binding affinity (-8.75 kcal/mol) to EGFR kinase compared to naringenin (-7.43 kcal/mol), with dynamics simulations confirming stable interactions beyond 100 ns. In vitro, both compounds significantly reduced HCT116 cell proliferation dose-dependently and exhibited robust antioxidant activity in the DPPH assay. In vivo, boldine and naringenin counteracted DMH-induced lipid imbalances (by reducing serum cholesterol, LDL, VLDL, and TG levels, with a simultaneous increase in HDL) and modulated oxidative stress (by decreasing malondialdehyde and restoring glutathione, superoxide dismutase, and catalase levels; p<0.05). Histopathological analysis showed that both compounds, restoring nearnormal colon architecture, markedly alleviated DMH-induced hyperplastic polyps and crypt distortions.

Discussion: Boldine and naringenin demonstrated chemopreventive potential by regulating lipid metabolism, bolstering antioxidant defenses, and preserving colon tissue integrity. Their strong EGFR interactions suggest utility as complementary therapies in CRC management, though further clinical validation is required to confirm their therapeutic potential.

Conclusion: Boldine and naringenin effectively attenuated DMH-induced colorectal carcinogenesis by modulating lipid profiles, reducing oxidative stress, and mitigating histological abnormalities. Their multifaceted mechanisms highlight their promise as adjuvant therapies for CRC, necessitating further clinical studies.