Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Apatinib has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma. Preclinical and preliminary clinical results confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) inhibitors. In this study, we investigated camptothecin (CPT) enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma. CPT combined with a PD-1 inhibitor enhances the anti-tumor effects of low-dose apatinib in hepatocellular carcinoma which was evaluated in making use of the H22 mouse model (n = 32), which was divided into four groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). The results showed that the average size of the tumor of the combination group (Group D) was significantly less than that of the apatinib + PD-1 inhibitor group (Group C). The expression levels of Nrf2, p62, VEGFA, VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group(Group C) were lower than those in the control group (Group A) (P < 0.05). The expression levels of these genes in the apatinib + PD-1 inhibitor group (Group C) were significantly lower in the combination group (Group D) (P < 0.05). There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT improves the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma.

Camptothecin improves sorafenib sensitivity by inhibiting Nrf2­ARE pathway in hepatocellular carcinoma.

Sorafenib is a targeted drug for hepatocellular carcinoma (HCC), however, its efficacy is limited. Nuclear factor erythroid 2­related factor 2 (Nrf2) contributes to sorafenib resistance. The present study investigated camptothecin (CPT) as a Nrf2 inhibitor to sensitize HCC to sorafenib. The effect of CPT on sorafenib sensitivity in HCC was assessed in vivo using H22 mice model (n=32) and VX2 rabbit models (n=32), which were sorted into four treatment groups. The expression levels of Nrf2, its downstream genes, including heme oxygenases­1 (HO­1) and NAD(P)H quinone oxidoreductase 1 (NQO1), and the epithelial­mesenchymal transition markers Snail and N­cadherin in tumors were determined using immunohistochemical staining and western blotting. Magnetic resonance imaging was used to monitor changes in tumor microcirculation and activity before and after treatment. Mouse body weights, liver and kidney function were monitored to evaluate the safety of combined therapy. The results revealed that the mean tumor size of the combined group was significantly smaller than that of sorafenib group for both models. The expression levels of Nrf2, heme oxygenase­1, NAD(P)H quinone oxidoreductase 1, Snail, and N­cadherin in the sorafenib group were significantly higher than control group (P<0.05). However, the expression levels of these genes were decreased in the combined group (P<0.05). Microcirculation perfusion and tumor activity in the combined group were also lower than sorafenib group. There were no significant differences in mouse body weight or liver and kidney function among the four groups. In summary, CPT is a Nrf2 inhibitor that could enhance the efficacy of sorafenib against HCC.

Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma.

Ferroptosis is a type of controlled cell death caused by lipid peroxidation, which results in the rupture of the cell membrane. ferroptosis has been repeatedly demonstrated over the past ten years to be a significant factor in a number of diseases. The liver is a significant iron storage organ, thus ferroptosis will have great potential in the treatment of liver diseases. Ferroptosis is particularly prevalent in HCC. In the opening section of this article, we give a general summary of the pertinent molecular mechanisms, signaling pathways, and associated characteristics of ferroptosis. The primary regulating mechanisms during ferroptosis are then briefly discussed, and we conclude by summarizing the development of a number of novel therapeutic strategies used to treat HCC in recent years. Ferroptosis is a crucial strategy for the treatment of HCC and offers new perspectives on the treatment of liver cancer.

Lenvatinib plus transarterial chemoembolization with or without immune checkpoint inhibitors for unresectable hepatocellular carcinoma: A review.

Lenvatinib plus transarterial chemoembolization (TACE)have become the first choice for patients with hepatocellular carcinoma (HCC) that are unsuitable for TACE. Sorafenib plus TACE therapy for patients with portal vein tumor thrombus (PVTT) achieved positive results. However, Lenvatinib plus TACE appeared to achieve a more advantageous result for these patients based on the phase 3 REFLECT trial. Both TACE and lenvatinib therapy have immune-stimulating effects, so would lenvatinib plus TACE and immune checkpoint inhibitors be an advantageous therapy for unresectable HCC (uHCC)? Thirteen articles from PubMed were explored to determine the efficacy and safety of lenvatinib plus TACE with or without PD-1 inhibitors therapy. Most of the adverse events (AEs) were manageable. Lenvatinib plus TACE therapy was superior to lenvatinib monotherapy with intermediate stage HCC especially beyond up-to-seven criterion and was superior to TACE monotherapy in patients with uHCC or sorafenib plus TACE therapy in patients with PVTT. Objective response rates (ORRs) of 53.1%-75%, median progression free survival (PFS) of 6.15-11.6 months, and median overall survival (OS) of 14.5-18.97 months were achieved in the lenvatinib plus TACE group. Levatinib plus TACE and PD-1 inhibitors achieved ORRs of 46.7% -80.6%, median PFS of 7.3-13.3 months, and median OS of 16.9-24 months. Control studies also confirmed the triple therapy was superior to lenvatinib plus TACE in patients with uHCC. Overall, the triple therapy is a promising treatment for patients with uHCC, including main PVTT and extrahepatic metastasis. Lenvatinib plus TACE therapy was also preferable for intermediate stage HCC beyond up-to-seven criterion and for patients with PVTT.

Experimental study of camptothecin combined with drug-eluting bead transarterial chemoembolization in the rabbit VX2 liver tumor model.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) has been widely used in the treatment of liver cancer; however, the utilization rate of chemotherapeutic drugs after embolization is low. Chemotherapy resistance mediated by high nuclear factor E2-related factor 2 (NRF2) expression limits DEB-TACE efficacy. Camptothecin (CPT), an NRF2 inhibitor, exerts chemosensitizing effects. We designed a controlled experiment to determine the efficacy and feasibility of DEB-TACE combined with CPT for the treatment of rabbit VX2 hepatoma. DEB-TACE activated NRF2 expression in the tumor region. NRF2 activation could be inhibited by the combined use of CPT. After DEB-TACE alone, the tumor necrosis was incomplete, there were still highly active tumor residues, and the apparent diffusion coefficient (ADC) value, which was negatively correlated with tumor activity observed by magnetic resonance imaging, remained low. After DEB-TACE combined with CPT, the relative necrosis of the tumor was more complete, the ADC value was higher, and the ADC change was greater. The single application of CPT did not result in evident liver function and physical burden to the rabbits. The combined use of CPT and DEB-TACE did not significantly increase DEB-TACE imaging of liver function and body. In conclusion, CPT can also inhibit high NRF2 expression after DEB-TACE treatment. Combining CPT with DEB-TACE can improve the sensitivity of DEB-TACE in the treatment of VX2 tumors, improve the therapeutic effect, and has no evident toxic and side effects. This study explored the methods for enhancing the efficacy of DEB-TACE in liver cancer from a new perspective and performed model experiments, which provided a theoretical basis for future clinical treatment.

Nrf2 Down-Regulation by Camptothecin Favors Inhibiting Invasion, Metastasis and Angiogenesis in Hepatocellular Carcinoma.

Higher oxidant stress capacity could promote invasion and metastasis. A previous study showed hepatocellular carcinoma (HCC) expressed more Nrf2 than para-carcinoma tissue. The chemotherapeutics such as epirubicin (EPI) could increase Nrf2 expression, while Camptothecin (CPT) could inhibit tumor growth by down-regulating the key molecule of antioxidant stress signal-Nrf2. The role of Nrf2 in invasion and metastasis was still unclear. In this study, we use EPI and CPT to determine the invasion and metastasis in Huh7 cells, H22 and Huh7 mouse models. In Huh7 cells, Nrf2 expression and ROS level were found increased after incubation with EPI by western blot and flow cytometry assay. But with the combination of EPI and CPT, inhibition of Nrf2 could decrease proliferation, invasion, and metastasis, which were investigated by CCK8 assay, wound healing, and Transwell assays. In Huh7 and H22 mouse models, EPI promoted Nrf2 up-regulation and nucleus translocation. Tumor growth was obviously inhibited with a single application of EPI or CPT. The combination of EPI and CPT could inhibit Nrf2 expression but demonstrated more suppressing effect of tumor growth than EPI. Western blot and immunohistochemical staining study revealed that Nrf2 inhibition was beneficial in decreasing the expression of N-cadherin, MMP9, Snail as well as Twist, and increasing E-cadherin, which were associated with epithelial-mesenchymal transition (EMT). Nrf2 down-regulation promoted lung metastasis of H22 cells in vivo. In addition, H&E staining and immunofluorescence staining of VEGFR suggested angiogenesis of Huh7 and H22 tumors was reduced. In conclusion, down-regulation of Nrf2 demonstrated inhibition of invasion, metastasis, and angiogenesis of hepatoma, which may provide a potential therapy in HCC.