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Updated: Jul 28, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Norcantharidin potentiates sorafenib antitumor activity in hepatocellular carcinoma rat model through inhibiting
Eman H Yousef1, Nada F Abo El-Magd2, Amal M El Gayar2
1Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, Damietta, Egypt.
Abstract:
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.
Insights
Norcantharidin (NCTD) enhances sorafenib (Sora) efficacy in hepatocellular carcinoma (HCC) by inhibiting IL-6. This combination therapy overcomes drug resistance, reactivates anti-tumor immunity, and reduces angiogenesis and metastasis.
Area of Science:
- Hepatocellular Carcinoma Research
- Drug Resistance Mechanisms
- Immunotherapy
Background:
- Sorafenib (Sora) efficacy in hepatocellular carcinoma (HCC) is often limited by drug resistance.
- Interleukin 6 (IL-6) is implicated as a key inflammatory factor contributing to Sora resistance.
- Norcantharidin (NCTD), an IL-6 inhibitor, presents a potential strategy to overcome this resistance.
Purpose of the Study:
- To investigate the efficacy of NCTD in combination with Sora for treating HCC.
- To elucidate the underlying molecular mechanisms by which NCTD enhances Sora's activity.
- To evaluate the impact of NCTD/Sora combination on tumor immunity, angiogenesis, metastasis, drug resistance, and stemness in HCC.
Main Methods:
- Hepatocellular carcinoma was induced in male Sprague Dawely rats using thioacetamide.
- Rats were treated with NCTD, Sora, or a combination of both for six weeks.
- Key molecular markers related to inflammation, immunity, angiogenesis, metastasis, drug resistance, proliferation, and apoptosis were analyzed.
Main Results:
- NCTD significantly enhanced Sora's anti-cancer activity and potentiated Sora-induced oxidative stress.
- The combination therapy reactivated anti-tumor immunity by modulating fibrinogen-like protein 1 (FGL1) and tumor necrosis factor-α (TNF-α) expression, and increasing CD8+ T cells.
- NCTD/Sora suppressed angiogenesis and metastasis by reducing VEGFA, HIF-1α, lactate dehydrogenase, and vimentin levels, while also overcoming drug resistance and stemness by downregulating ABCG2, Notch, STAT4, and CD133.
Conclusions:
- This study provides the first evidence for the novel therapeutic potential of combining NCTD and Sora for HCC treatment.
- NCTD demonstrates a significant ability to improve Sora efficacy by targeting IL-6 mediated resistance pathways.
- The combination therapy exhibits broad anti-tumor effects, including immune reactivation, inhibition of angiogenesis and metastasis, and suppression of drug resistance and stemness.
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