Thymoquinone, piperine, and sorafenib combinations attenuate liver and breast cancers progression: epigenetic and molecular docking approaches.

BACKGROUND: Traditional herbal medicine has been used for centuries to cure many pathological disorders, including cancer. Thymoquinone (TQ) and piperine (PIP) are major bioactive constituents of the black seed (Nigella sativa) and black pepper (Piper nigrum), respectively. The current study aimed to explore the potential chemo-modulatory effects, mechanisms of action, molecular targets, and binding interactions after TQ and PIP treatments and their combination with sorafenib (SOR) against human triple-negative breast cancer (MDA-MB-231) and liver cancer (HepG2) cells. METHODS: We determined drug cytotoxicity by MTT assay, cell cycle, and death mechanism by flow cytometry. Besides, the potential effect of TQ, PIP, and SOR treatment on genome methylation and acetylation by determination of DNA methyltransferase (DNMT3B), histone deacetylase (HDAC3) and miRNA-29c expression levels. Finally, a molecular docking study was performed to propose potential mechanisms of action and binding affinity of TQ, PIP, and SOR with DNMT3B and HDAC3. RESULTS: Collectively, our data show that combinations of TQ and/or PIP with SOR have significantly enhanced the SOR anti-proliferative and cytotoxic effects depending on the dose and cell line by enhancing G2/M phase arrest, inducing apoptosis, downregulation of DNMT3B and HDAC3 expression and upregulation of the tumor suppressor, miRNA-29c. Finally, the molecular docking study has identified strong interactions between SOR, PIP, and TQ with DNMT3B and HDAC3, inhibiting their normal oncogenic activities and leading to growth arrest and cell death. CONCLUSION: This study reported TQ and PIP as enhancers of the antiproliferative and cytotoxic effects of SOR and addressed the mechanisms, and identified molecular targets involved in their action.

Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma.

PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Driving role of head and neck cancer cell secretome on the invasion of stromal fibroblasts: Mechanistic insights by phosphoproteomics.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are major players in tumor-stroma communication, and participate in several cancer hallmarks to drive tumor progression and metastatic dissemination. This study investigates the driving effects of tumor-secreted factors on CAF biology, with the ultimate goal of identifying effective therapeutic targets/strategies for head and neck squamous cell carcinomas (HNSCC). METHODS: Functionally, conditioned media (CM) from different HNSCC-derived cell lines and normal keratinocytes (Kc) were tested on the growth and invasion of populations of primary CAFs and normal fibroblasts (NFs) using 3D invasion assays in collagen matrices. The changes in MMPs expression were evaluated by RT-qPCR and kinase enrichment was analyzed using mass spectrometry phosphoproteomics. RESULTS: Our results consistently demonstrate that HNSCC-secreted factors (but not Kc CM) specifically and robustly promoted pro-invasive properties in both CAFs and NFs, thereby reflecting the plasticity of fibroblast subtypes. Concomitantly, HNSCC-secreted factors massively increased metalloproteinases levels in CAFs and NFs. By contrast, HNSCC CM and Kc CM exhibited comparable growth-promoting effects on stromal fibroblasts. Mechanistically, phosphoproteomic analysis predominantly revealed phosphorylation changes in fibroblasts upon treatment with HNSCC CM, and various promising kinases were identified: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Interestingly, pharmacologic inhibition of RAF1/BRAF using sorafenib emerged as the most effective drug to block tumor-promoted fibroblast invasion without affecting fibroblast viability CONCLUSIONS: Our findings demonstrate that HNSCC-secreted factors specifically fine tune the invasive potential of stromal fibroblasts, thereby generating tumor-driven pro-invasive niches, which in turn to ultimately facilitate cancer cell dissemination. Furthermore, the RAF/BRAF inhibitor sorafenib was identified as a promising candidate to effectively target the onset of pro-invasive clusters of stromal fibroblasts in the HNSCC microenvironment.

An Angiogenic Gene Signature for Prediction of the Prognosis and Therapeutic Responses of Hepatocellular Carcinoma.

Among cancer-related deaths worldwide, hepatocellular carcinoma (HCC) ranks second. The hypervascular feature of most HCC underlines the importance of angiogenesis in therapy. This study aimed to identify the key genes which could characterize the angiogenic molecular features of HCC and further explore therapeutic targets to improve patients' prognosis. Public RNAseq and clinical data are from TCGA, ICGC, and GEO. Angiogenesis-associated genes were downloaded from the GeneCards database. Then, we used multi-regression analysis to generate a risk score model. This model was trained on the TCGA cohort (n = 343) and validated on the GEO cohort (n = 242). The predicting therapy in the model was further evaluated by the DEPMAP database. We developed a fourteen-angiogenesis-related gene signature that was distinctly associated with overall survival (OS). Through the nomograms, our signature was proven to possess a better predictive role in HCC prognosis. The patients in higher-risk groups displayed a higher tumor mutation burden (TMB). Interestingly, our model could group subsets of patients with different sensitivities to immune checkpoint inhibitors (ICIs) and Sorafenib. We also predicted that Crizotinib, an anti-angiogenic drug, might be more sensitive to these patients with high-risk scores by the DEPMAP. The inhibitory effect of Crizotinib in human vascular cells was obvious in vitro and in vivo. This work established a novel HCC classification based on the gene expression values of angiogenesis genes. Moreover, we predicted that Crizotinib might be more effective in the high-risk patients in our model.

A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia.

Despite incredible progress in cancer treatment, therapy resistance remains the leading limiting factor for long-term survival. During drug treatment, several genes are transcriptionally upregulated to mediate drug tolerance. Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity prediction model for the receptor tyrosine kinase inhibitor sorafenib and achieved more than 80% prediction accuracy. Furthermore, by using Shapley additive explanations for determining leading features, we identified AXL as an important feature for drug resistance. Drug-resistant patient samples displayed enrichment of protein kinase C (PKC) signaling, which was also identified in sorafenib-treated FLT3-ITD-dependent AML cell lines by a peptide-based kinase profiling assay. Finally, we show that pharmacological inhibition of tyrosine kinase activity enhances AXL expression, phosphorylation of the PKC-substrate cyclic AMP response element binding (CREB) protein, and displays synergy with AXL and PKC inhibitors. Collectively, our data suggest an involvement of AXL in tyrosine kinase inhibitor resistance and link PKC activation as a possible signaling mediator.

Proto-Oncogene FAM50A Can Regulate the Immune Microenvironment and Development of Hepatocellular Carcinoma In Vitro and In Vivo.

Hepatocellular carcinoma (HCC) is a vital global health problem. The characteristics are high morbidity, high mortality, difficulty in early diagnosis and insensitivity to chemotherapy. The main therapeutic schemes for treating HCC mainly include Tyrosine kinase inhibitors represented by sorafenib and lenvatinib. In recent years, immunotherapy for HCC has also achieved certain results. However, a great number of patients failed to benefit from systemic therapies. FAM50A belongs to the FAM50 family and can be used as a DNA-binding protein or transcription factor. It may take part in the splicing of RNA precursors. In studies of cancer, FAM50A has been demonstrated to participate in the progression of myeloid breast cancer and chronic lymphocytic leukemia. However, the effect of FAM50A on HCC is still unknown. In this study, we have demonstrated the cancer-promoting effects and diagnostic value of FAM50A in HCC using multiple databases and surgical samples. We identified the role of FAM50A in the tumor immune microenvironment (TIME) and immunotherapy efficacy in HCC. We also proved the effects of FAM50A on the malignancy of HCC in vitro and in vivo. In conclusion, we confirmed that FAM50A is an important proto-oncogene in HCC. FAM50A acts as a diagnostic marker, immunomodulator and therapeutic target for HCC.

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing.

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Hepatitis B virus (HBV) infection accounts for nearly 50% of HCC cases. Recent studies indicate that HBV infection induces resistance to sorafenib, the first-line systemic treatment for advanced HCC for more than a decade, from 2007 to 2020. Our previous research shows that variant 1 (tv1) of proliferating cell nuclear antigen clamp-associated factor (PCLAF), overexpressed in HCC, protects against doxorubicin-induced apoptosis. However, there are no reports on the relevance of PCLAF in sorafenib resistance in HBV-related HCC. In this article, we found that PCLAF levels were higher in HBV-related HCC than in non-virus-related HCC using bioinformatics analysis. Immunohistochemistry (IHC) staining of clinical samples and the splicing reporter minigene assay using HCC cells revealed that PCLAF tv1 was elevated by HBV. Furthermore, HBV promoted the splicing of PCLAF tv1 by downregulating serine/arginine-rich splicing factor 2 (SRSF2), which hindered the inclusion of PCLAF exon 3 through a putative cis-element (116-123), "GATTCCTG". The CCK-8 assay showed that HBV decreased cell susceptibility to sorafenib through SRSF2/PCLAF tv1. HBV reduced ferroptosis by decreasing intracellular Fe2+ levels and activating GPX4 expression via the SRSF2/PCLAF tv1 axis, according to a mechanism study. Suppressed ferroptosis, on the other hand, contributed to HBV-mediated sorafenib resistance through SRSF2/PCLAF tv1. These data suggested that HBV regulated PCLAF abnormal alternative splicing by suppressing SRSF2. HBV caused sorafenib resistance by reducing ferroptosis via the SRSF2/PCLAF tv1 axis. As a result, the SRSF2/PCLAF tv1 axis may be a prospective molecular therapeutic target in HBV-related HCC, as well as a predictor of sorafenib resistance. The inhibition of the SRSF2/PCLAF tv1 axis may be crucial in the emergence of systemic chemotherapy resistance in HBV-associated HCC.

XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial-mesenchymal transition in hepatocellular carcinoma.

Emerging studies have suggested that exportin-1 (XPO1) plays a pivotal role in hepatocellular carcinoma (HCC). However, the underlying mechanism of XPO1 in HCC sorafenib resistance remains enigmatic. The expression of XPO1 in HCC tumor tissues and sorafenib-resistant (SR) cells were analyzed by bioinformatics analysis, immunohistochemistry (IHC) and Western blotting. The interaction mechanism between XPO1 and Nucleophosmin (NPM1) was investigated by immunoprecipitation (IP), Mass-spectrometric (MS) analysis, immunofluorescence colocalization, CRISPR/CAS9 technology and RNA-seq. Analyses were also conducted on KPT-8602 and sorafenib's combined therapeutic effect. Our findings unraveled that the XPO1 overexpression was observed in HCC, and correlated with poorer survival. Knockdown of XPO1 inhibited the migration and proliferation of HCC cells, and also reduced the resistance of HCC cells to sorafenib. Mechanistically, XPO1 interacted with the C-terminus of NPM1 and mediated the acetylation of NPM1 at lysine 54 to maintain sorafenib resistance. XPO1 was bound to Vimentin, resulting in the epithelial-mesenchymal transition (EMT) progression in sorafenib-resistant cells. KPT-8602 in combination with sorafenib suppressed the tumor growth. These results highlighted the therapeutic value of targeting XPO1 in overcoming sorafenib resistance. The combinational treatment of KPT-8602 and sorafenib might be an improved therapeutic option.

A comprehensive computational analysis to explore the importance of SIGLECs in HCC biology.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive, malignant cancer with a complex pathogenesis. However, effective therapeutic targets and prognostic biomarkers are limited. Sorafenib provides delaying cancer progression and survival improvement in advanced HCC. But despite 10 years of research on the clinical application of sorafenib, predictive markers for its therapeutic effect are lacking. METHODS: The clinical significance and molecular functions of SIGLEC family members were assessed by a comprehensive bioinformatic analysis. The datasets included in this study (ICGC-LIRI-JP, GSE22058 and GSE14520) are mainly based on patients with HBV infections or HBV-related liver cirrhosis. The TCGA, GEO, and HCCDB databases were used to explore the expression of SIGLEC family genes in HCC. The Kaplan-Meier Plotter database was used to evaluate relationships between the expression levels of SIGLEC family genes and prognosis. Associations between differentially expressed genes in the SIGLEC family and tumour-associated immune cells were evaluated using TIMER. RESULTS: The mRNA levels of most SIGLEC family genes were significantly lower in HCC than in normal tissues. Low protein and mRNA expression levels of SIGLECs were strongly correlated with tumour grade and clinical cancer stage in patients with HCC. Tumour-related SIGLEC family genes were associated with tumour immune infiltrating cells. High SIGLEC expression was significantly related to a better prognosis in patients with advanced HCC treated with sorafenib. CONCLUSIONS: SIGLEC family genes have potential prognostic value in HCC and may contribute to the regulation of cancer progression and immune cell infiltration. More importantly, our results revealed that SIGLEC family gene expression may be used as a prognostic marker for HCC patients treated with sorafenib.

Donafenib in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global healthcare problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Sorafenib demonstrated its efficacy as the first therapeutic agent for unresectable HCC in 2007. Since then, other multitarget tyrosine kinase inhibitors have demonstrated efficacy in HCC patients. Still, the tolerability of these drugs remains an unsolved problem, with 5-20% of patients permanently discontinuing their therapies due to adverse events. Donafenib is a deuterated form of sorafenib exploiting the increased bioavailability derived from the deuterium-for-hydrogen replacement. In the multicenter, randomized, controlled phase II-III trial ZGDH3, donafenib outperformed sorafenib in terms of overall survival, with favorable safety and tolerability. As a result, donafenib was approved as a possible first-line treatment of unresectable HCC by the National Medical Products Administration (NMPA) of China in 2021. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of donafenib.

Potent nanoreactor-mediated ferroptosis-based strategy for the reversal of cancer chemoresistance to Sorafenib.

The drug resistance of cancer cells is related to a variety of mechanisms, among which the destruction of redox homeostasis is one of the key factors. Ferroptosis, an intracellular iron-dependent form of cell death, is related to the production of oxidative stress. The accumulation of lipid peroxidation (LPO) during ferroptosis disrupts intracellular redox homeostasis, thereby affecting the sensitivity of tumor cells to drugs. In this work, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein and inactivated glutathione peroxidase 4 (GPX4) to reverse the chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO, but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'. The study proposed the mechanism and feasibility of ferroptosis to reverse drug resistance, providing a promising strategy for chemo-resistant cancer treatment. STATEMENT OF SIGNIFICANCE: Herein, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein, and inactivated glutathione peroxidase 4 (GPX4) to reverse chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'.

TKIs in combination with immunotherapy for hepatocellular carcinoma.

INTRODUCTION: The treatment landscape of hepatocellular carcinoma (HCC) has significantly changed over the last 5 years with multiple options in the frontline, second line, and beyond. Tyrosine kinase inhibitors (TKIs) were the first approved systemic treatments for the advanced stage of HCC; however, thanks to the increasing knowledge and characterization of the immunological features of the tumor microenvironment, the systemic treatment of HCC has been further expanded with the immune checkpoint inhibitor (ICI) approach and the following evidence of the higher efficacy obtained with combined treatment with atezolizumab plus bevacizumab over sorafenib. AREAS COVERED: In this review, we look at rationale, efficacy, and safety profiles of current and emerging ICI/TKI combination treatments and discuss the available results from other clinical trials using similar combinatorial therapeutic approaches. EXPERT OPINION: Angiogenesis and immune evasion are the two key pathogenic hallmarks of HCC. While the pioneering regimen of atezolizumab/bevacizumab is consolidating as the first-line treatment of advanced HCC, it will be essential, in the near future, to determine the best second-line treatment options and how to optimize the selection of the most effective therapies. These points still need to be addressed by future studies that are largely warranted to enhance the treatment's effectiveness and ultimately to tackle down HCC lethality.

Clinical characteristics and outcome of patients with combined hepatocellular-cholangiocarcinoma-a European multicenter cohort.

BACKGROUND: There is no clear consensus on the optimal systemic treatment regimen in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. We describe clinical characteristics and outcome of cHCC-CCA patients, with a special focus on patients receiving palliative systemic therapy, including immune checkpoint inhibitors (ICIs). METHODS: In this European retrospective, multicenter study, patients with histologically proven cHCC-CCA treated at four institutions between April 2003 and June 2022 were included. In patients receiving palliative systemic therapy, outcome was compared between cytotoxic chemotherapy (CHT)- and non-cytotoxic CHT (nCHT)-treated patients. RESULTS: Of 101 patients, the majority were male (n = 70, 69%) with a mean age of 64.6 ± 10.6 years. Only type of first-line treatment was independently associated with overall survival (OS). Palliative systemic therapy was administered to 44 (44%) patients. Of those, 25 (57%) patients received CHT and 19 (43%) had nCHT (n = 16 of them sorafenib) in systemic first line. Although there was no significant difference in overall response rate (ORR; CHT versus nCHT: 8% versus 5%), disease control rate (24% versus 21%), and median progression-free survival {3.0 months [95% confidence interval (CI) 1.4-4.6 months] versus 3.2 months (95% CI 2.8-3.6 months), P = 0.725}, there was a trend towards longer median OS in the CHT group [15.5 months (95% CI 8.0-23.0 months) versus 5.3 months (95% CI 0-12.5 months), P = 0.052]. However, in multivariable analysis, type of first-line regimen (CHT versus sorafenib) was not associated with OS. ORR in patients receiving ICIs (n = 7) was 29%. CONCLUSIONS: In patients with cHCC-CCA, OS, progression-free survival, ORR, and disease control rate were not significantly different between individuals receiving CHT and patients receiving nCHT. Immunotherapy may be effective in a subset of patients. Prospective studies are needed to identify optimal systemic treatment regimens in cHCC-CCA.

Real-world systemic sequential therapy with regorafenib for recurrent hepatocellular carcinoma: analysis of 93 cases from a single center.

BACKGROUND: Regorafenib is an oral multikinase inhibitor and became the first second-line systemic treatment for hepatocellular carcinoma (HCC) following the phase III RESORCE trial. This single-center study retrospectively analyzed the clinical data and follow-up results of patients with recurrent HCC treated with regorafenib and discussed the prognostic factors to provide guidance for clinical treatment. METHODS: Ninety-three recurrent HCC patients were enrolled in the research and follow up from December 2017 to December 2020. Clinical and pathological data were collected. SPSS software v26.0 was used (Chicago, IL, USA) for statistical analysis. A two-sided P < 0.05 was considered statistically significant. RESULTS: The patients included 81 males and 12 females with a median age of 57 years. Eighty-seven patients had hepatitis B virus (HBV) infection. The objective response rate (ORR) was 14.0%, and the disease control rate (DCR) was 62.4%. The median overall survival (mOS) and median time to progression (mTTP) were 15.9 and 5.0 months. Multivariate analysis showed that Child-Pugh classification, the Eastern Cooperative Oncology Group performance status (ECOG PS), the neutrophil-to-lymphocyte ratio (NLR), combined treatment, and the time from first diagnosis of HCC to second-line treatment were independent factors affecting the prognosis of recurrent HCC patients. CONCLUSIONS: This real-world study demonstrated similar findings to those of the RESORCE trial. Regorafenib could effectively improve the prognosis of patients after first-line treatment failure. Combination therapy under multidisciplinary treatment (MDT) team guidance could be effective in impeding tumor progression and improving the prognosis of recurrent HCC patients.

A meta-analysis of the efficacy and toxicity of tyrosine kinase inhibitors in treating patients with different types of thyroid cancer: how to choose drugs appropriately?

PURPOSE OF REVIEW: Because the high risk of death and poor prognosis of patients with refractory thyroid cancer (TC), studies related to tyrosine kinase inhibitors (TKIs) in treating different types of refractory TC have gradually attracted attention. Thus, we conducted a meta-analysis of published randomized controlled trials and single-arm trials to evaluate tyrosine kinase inhibitors' efficacy and safety profile treatment in TC patients. RECENT FINDINGS: The studies of 29 in 287 met the criteria, 9 were randomized controlled trials and 20 were single-arm trials, involving 11 TKIs (Apatinib, Anlotinib, Cabozantinib, Imatinib, Lenvatinib, Motesanib, Pazopanib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib). Treatment with TKIs significantly improved progression-free survival [hazard ratio [HR] 0.34 (95% confidence interval [CI]: 0.24, 0.48), P < 0.00001] and overall survival [OS] [HR 0.76, (95% CI: 0.64, 0.91), P = 0.003] in randomized controlled trials, but adverse events (AEs) were higher than those in the control group (P < 0.00001). The result of the objective response rate (ORR) in single-arm trials was statistically significant [odds ratio [OR] 0.49 (95% CI: 0.32, 0.75), P = 0.001]. SUMMARY: TKIs significantly prolonged progression-free survival and OS or improved ORR in patients with different types of TC (P < 0.01). Our recommendation is to select appropriate TKIs to treat different types of TC patients, and to prevent and manage drug-related AEs after using TKIs.

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.

Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma.

Ferroptosis is potential to relieve drug resistance in hepatocellular carcinoma (HCC). Glutathione peroxidase 4 (GPX4) is a critical modulator of ferroptosis. This study discussed the mechanism of GPX4-inhibited ferroptosis in sorafenib resistance in HCC. HCG18 in HCC cells was detected. Sorafenib resistant (SR) cell line Huh7-SR cells were treated with sorafenib (0, 2.5, 5, 7.5, 10 µM). After silencing HCG18 in Huh7-SR cells, cell activity, proliferation and apoptosis were detected. The levels of iron, the concentration of MDA, GSH and lipid reactive oxygen species (ROS) were measured to evaluate the ferroptosis. The downstream mechanism of HCG18 was predicted and verified. Huh7-SR cells were infected with lentivirus sh-HCG18 to establish xenograft tumor model. HCG18 was elevated in HCC cells and associated with sorafenib resistance. Silencing HCG18 inhibited cell proliferation, promoted apoptosis, and impaired sorafenib resistance. Ferroptosis was inhibited in Huh7-SR cells, while silencing HCG18 inhibited sorafenib resistance by promoting ferroptosis. GPX4 overexpression averted the promotion of sh-HCG18 on ferroptosis, thereby reducing sorafenib resistance. HCG18 sponged miR-450b-5p to regulate GPX4. Collectively, Silencing HCG18 inhibits GPX4 by binding to miR-450b-5p, promotes GPX4-inhibited ferroptosis, and averts sorafenib resistance in HCC.

Ca2+-Dependent Effects of the Selenium-Sorafenib Nanocomplex on Glioblastoma Cells and Astrocytes of the Cerebral Cortex: Anticancer Agent and Cytoprotector.

Despite the fact that sorafenib is recommended for the treatment of oncological diseases of the liver, kidneys, and thyroid gland, and recently it has been used for combination therapy of brain cancer of various genesis, there are still significant problems for its widespread and effective use. Among these problems, the presence of the blood-brain barrier of the brain and the need to use high doses of sorafenib, the existence of mechanisms for the redistribution of sorafenib and its release in the brain tissue, as well as the high resistance of gliomas and glioblastomas to therapy should be considered the main ones. Therefore, there is a need to create new methods for delivering sorafenib to brain tumors, enhancing the therapeutic potential of sorafenib and reducing the cytotoxic effects of active compounds on the healthy environment of tumors, and ideally, increasing the survival of healthy cells during therapy. Using vitality tests, fluorescence microscopy, and molecular biology methods, we showed that the selenium-sorafenib (SeSo) nanocomplex, at relatively low concentrations, is able to bypass the mechanisms of glioblastoma cell chemoresistance and to induce apoptosis through Ca2+-dependent induction of endoplasmic reticulum stress, changes in the expression of selenoproteins and selenium-containing proteins, as well as key kinases-regulators of oncogenicity and cell death. Selenium nanoparticles (SeNPs) also have a high anticancer efficacy in glioblastomas, but are less selective, since SeSo in cortical astrocytes causes a more pronounced activation of the cytoprotective pathways.