Preclinical evidence for preventive and curative effects of resveratrol on xenograft cholangiocarcinogenesis

Suyanee Thongchot  ¹ , Alessandra Ferraresi  ² , Chiara Vidoni  ² , Amreen Salwa  ² , Letizia Vallino  ² , Yingpinyapat Kittirat  ³ , Watcharin Loilome  ⁴ , Nisana Namwat  ⁵ , Ciro Isidoro  ⁶

Affiliations

Affiliations

• ¹ Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100, Novara, Italy; Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
• ² Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100, Novara, Italy.
• ³ Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Department of Medical Sciences, Regional Medical Sciences Center 2 Phitsanulok, Ministry of Public Health, Phitsanulok, Thailand.
• ⁴ Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand.
• ⁵ Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen, 40002, Thailand. Electronic address: nisana@kku.ac.th.
• ⁶ Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100, Novara, Italy. Electronic address: ciro.isidoro@med.uniupo.it.

• PMID: 38097133
• DOI: 10.1016/j.canlet.2023.216589

Abstract

Cholangiocarcinoma (CCA), the malignant tumor of bile duct epithelial cells, is a relatively rare yet highly lethal cancer. In this work, we tested the ability of Resveratrol (RV) to prevent and cure CCA xenograft in nude mice and investigated molecular mechanisms underpinning such anticancer effect. Human CCA cells were xenografted in mice that were or not treated prior to or after to transplantation with RV. Tumor growth was monitored and analyzed for the markers of cell proliferation, apoptosis, and autophagy. TCGA was interrogated for the molecules possibly targeted by RV. RV could inhibit the growth of human CCA xenograft when administered after implantation and could reduce the growth or even impair the implantation of the tumors when administered prior the transplantation. RV inhibited CCA cell proliferation, induced apoptosis with autophagy, and strongly reduced the presence of CAFs and production of IL-6. Interrogation of CCA dataset in TCGA database revealed that the expression of IL-6 Receptor (IL-6R) inversely correlated with that of MAP-LC3 and BECLIN-1, and that low expression of IL-6R and of MIK67, two pathways downregulated by RV, associated with better survival of CCA patients. Our data demonstrate that RV elicits a strong preventive and curative anticancer effect in CCA by limiting the formation of CAFs and their release of IL-6, and this results in up-regulation of autophagy and apoptosis in the cancer cells. These findings support the clinical use of RV as a primary line of prevention in patients exposed at risk and as an adjuvant therapeutics in CCA patients.

Keywords: Autophagy; Cancer associated fibroblasts; Cholangiocarcinoma; Nutraceuticals; tumor microenvironment.