Norcantharidin potentiates sorafenib antitumor activity in hepatocellular carcinoma rat model through inhibiting IL-6/STAT3 pathway.

Autor: Yousef EH; Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, Damietta, Egypt. Electronic address: ehamdy@horus.edu.eg., El-Magd NFA; Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., El Gayar AM; Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: elgayaramal@gmail.com.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2023 Oct; Vol. 260, pp. 69-82. Date of Electronic Publication: 2023 May 30.
DOI: 10.1016/j.trsl.2023.05.005
Abstrakt: In hepatocellular carcinoma (HCC), sorafenib (Sora) efficacy is limited by primary and/or acquired resistance. Emerging evidence shows that the inflammatory factor interleukin 6 (IL-6) plays a role in Sora resistance. Norcantharidin (NCTD), a derivative of cantharidine, was identified as a potent IL-6 inhibitor. Thus, in this study, we evaluated NCTD ability to improve the Sora efficacy in HCC and its underlying molecular mechanisms. Male Sprague Dawely rats were administered NCTD (0.1 mg/kg/day; orally) or Sora (10 mg/kg day; orally) or combination for 6 weeks after HCC induction using thioacetamide (200 mg/kg; ip; 2 times/wk) for 16 weeks. Our results showed that NCTD greatly enhanced Sora activity against HCC and potentiated Sora-induced oxidative stress. NCTD enhanced Sora-induced tumor immunity reactivation by decreasing both fibrinogen-like protein 1 level and increasing both tumor necrosis factor-α gene expression along with CD8+ T cells number. Also, NCTD augmented Sora attenuation activity against TAA-induced angiogenesis and metastasis by decreasing VEGFA, HIF-1α, serum lactate dehydrogenase enzyme, and vimentin levels. The combined use of NCTD/Sora suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, neurogenic locus notch homolog protein, spalt-like transcription factor 4, and CD133. NCTD boosted Sora antiproliferative and apoptotic activities by decreasing Ccnd1 and BCL2 expressions along with increasing BAX and caspase-3 expressions. To our knowledge, this study represents the first study providing evidence for the potential novel therapeutic use of NCTD/Sora combination for HCC. Moreover, no previous studies have reported the effect of NCTD on FGL1.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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