Search

Currently, many challenges are associated with hepatocellular carcinoma (HCC) as the failure of early diagnosis, and the lack of effective therapy. This study aimed to investigate the possible role of tuftelin 1 (TUFT 1) in the early diagnosis of HCC and evaluate the potential contribution of the TUFT 1/Ca +2 /phosphinositol 3 kinase (PI3K) pathway in dantrolene sodium (Dan) therapeutic outcomes. The study was performed on two sets of rats, the staging (30 rats) and treatment sets (80 rats). HCC was induced by a single dose of diethylnitrosamine (DENA). The hepatic content of TUFT 1 protein was assayed via western blot and immunohistochemistry (IHC), while PI3K, vascular endothelial growth factor (VEGF), Cyclin D1, and matrix-metalloproteinase-9 (MMP-9) contents were assessed using enzyme-linked immunosorbent assay. Hepatic and serum calcium were measured colorimetrically. Furthermore, the nuclear proliferation marker, (Ki-67), (Kiel [Ki] where the antibody was produced in the University Department of Pathology and the original clone number is 67)-expression was assessed by IHC. TUFT 1/Ca +2 /PI3K signaling pathway was progressively activated in the 3 studied stages of HCC with subsequent upregulation of angiogenesis, cell cycle, and metastasis. More interestingly, Dan led to TUFT 1/Ca +2 /PI3K pathway disruption by diminution of the hepatic contents of TUFT 1, calcium, PI3K, VEGF, Cyclin D1, and MMP-9 in a dose-dependent pattern. TUFT 1 can serve as a theranostic biomarker in HCC. Moreover, Dan exerted an antineoplastic effect against HCC via the interruption of TUFT 1/Ca +2 /PI3K pathway., (© 2023 John Wiley & Sons Ltd.)

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers, associated with a high rate of mortality. A disturbance between cell proliferation and cell death is one of the cancer hallmarks including HCC. Cell proliferation is mainly controlled by the cell cycle. The arrest of the cell cycle is one of the important targets of anticancer agents., Objectives: The present study tries to clarify the exact role of some natural products such as daidzein (DAZ) and alcoholic chicory leaf extract (CE), as possible regulators of cell cycle and apoptosis., Methods: HCC in rats was induced using diethylnitrosamine (DENA). Ninety rats were allocated and divided equally into nine groups, treated with CE, DAZ, a combination of both, and sorafenib with non-treated control groups., Results: Treatment with CE, DAZ, and their combination significantly downregulated hepatic tissue expression of cyclin D1/CDK4 axis as well as cyclin A/CDK2 axis. The suggested therapeutic protocol inhibited the proliferation and dampened Bcl-2 expression. Furthermore, the efficiency of combining CE and DAZ demonstrated a potency comparable to sorafenib in terms of cyclin D/CDK4 axis expression, as well as; this combination protocol was more potent in revealing a potentiated inhibitory effect on cyclin A and Ki-67 expression., Conclusion: Treatment with DAZ or CE alone, or in combination, could possess an inhibitory effect on hepatocarcinogenesis via cell cycle arrest, inhibition of proliferation through suppression of Ki-67 expression, and apoptosis induction, mediated by downregulation of Bcl-2., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance., Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway., Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically., Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib., Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hepatocellular carcinoma (HCC) is one of the most rapidly growing solid cancers, that is characterized by hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates tumor proliferation and metastasis. It induces caveolin-1 (Cav-1) expression, a glycoprotein found on the membrane surface, then Cav-1 triggers angiogenesis and metastasis in HCC., Objective: We hypothesize that targeting HIF-1α and consequently, Cav-1 using the antioxidant natural compound such as chicoric acid and a Cav-1 inhibitor daidzein (DAZ) could be a useful approach in the management of HCC. This study was conducted to investigate the possible therapeutic efficacy of standardized chicory leaf extract (SCLE) and DAZ via modulation of HIF-1α and Cav-1 in HCC rats., Methods: Diethyl nitrosamine (DENA) was used for HCC induction. After the induction period, four groups (10 rats for each) were treated with SCLE, DAZ, a combination of both, as well as sorafenib, all compared to the non-treated control. We assessed hepatic HIF-1α protein expression, Cav-1 gene expression, serum level of AFP, hepatic tissue content of VEGF, MMP-9, oxidative stress markers MDA and SOD., Results: DAZ, SCLE, and their combination, significantly down-regulated the expression of HIF-1α, Cav-1, and consequently dampened MMP-9, VEGF, hepatic content. It has been observed that the combination treatment showed a synergistic effect compared to either treatment alone. Importantly, the combination treatment exhibited a significantly more potent effect than sorafenib., Conclusion: This study showed the potential role of the HIF-1α/Cav-1 pathway in HCC progression, moreover, SCLE and DAZ showed a potent efficacy in retarding HCC via modulation of this pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hepatocellular carcinoma (HCC) is a main cause of cancer death all over the world. Treatment and outcome of HCC based on its early diagnosis. This study was conducted to estimate the role of talin-1 and midkine in combination with total antioxidant capacity (TAC) as tumor markers in HCC patients. Methods: Serum levels of talin-1 and midkine were measured in 90 Egyptian subjects including 44 patients with HCC, 31patients with cirrhosis and 15 healthy controls using enzyme-linked immunosorbent assay (ELISA) technique. While a colorimetric method was used for measurement of TAC. Results: Serum talin-1 in HCC patients was significantly lower than that in patients with cirrhosis (P<0.001) and normal control (P<0.001). In addition, increased invasion and metastasis correlated with reduced talin-1 level. Serum midkine in HCC patients was significantly higher compared to cirrhotic patients (P<0.001) and normal control (P<0.001). Midkine at a cut off value of 1683 pg/ml showed a sensitivity of (81.82%) and specificity of (83.87%). While alpha-fetoprotein (AFP) at a cut off value of 200 ng/ml had a sensitivity of (52.27%), while specificity was (96.77%). Midkine was positive in 80.9% of HCC patients with negative AFP. Serum TAC was significantly decreased in HCC patients when compared with control group (P<0.001). Conclusion: Talin-1 may be implicated in the carcinogenesis and metastasis of HCC and can be used as a useful tumor marker for HCC. Midkine may be a potential diagnostic marker for HCC and may be used in addition to AFP to increase the sensitivity of HCC detection., (Creative Commons Attribution License)

Aims: Wnt3a and Wnt5a are ligands orchestrating the canonical and non-canonical pathways, respectively, with involvement in hepatocellular carcinoma (HCC). Hesperidin (HP) is a natural product found in citrus fruits and reputed for its antitumor activity. The present study aims to investigate the potential hepatoprotective effect of HP against thioacetamide (TAA)-induced HCC focusing on its potential role on Wnt3a and Wnt5a signaling pathways., Main Methods: Forty rats were equally divided into groups; normal control, HP control (receiving HP, 150mg/kg/day), HCC (receiving TAA, 200mg/kg twice weekly for 14weeks) and HP-HCC (receiving HP and TAA). Gene expressions of Wnt3a, Wnt5a, β-catenin and Cyclin D1 were assessed by qPCR, while their protein levels, along with active caspase-3 level, were quantified by ELISA and immunohistochemistry. Liver functions, oxidative stress parameters and myeloperoxidase activity were measured. MTT assay of hepG2 cells treated with recombinant Wnt3a (10ng/ml) in presence or absence of HP (100μM) was performed., Key Findings: HCC group exhibited a significant increase in Wnt3a, β-catenin, Cyclin D1 and Wnt5a gene expressions, as well as, their protein levels. HP significantly prevented TAA-activated Wnt3a/β-catenin and Wnt5a pathways. Moreover, HP exerted hepatoprotective effect by significantly improving the oxidative imbalance, inflammation and liver function parameters, serum ALT, AST activities, and albumin level., Significance: Our study is the first to report the possible role of Wnt3a/β-catenin and Wnt5a pathways in TAA-induced early HCC model in rats. HP has a prophylactic effect against hepatocarcinogenesis via preventing the induction of both canonical and non-canonical Wnt pathways., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Angiogenesis plays important roles in progression of hepatocellular carcinoma. The antiangiogenic mechanisms of vitexicarpine are not fully defined. Therefore, we conducted the following study to evaluate the antiangiogenic mechanism and antitumor activity of vitexicarpine in vivo model of hepatocellular carcinoma through modulation of vascular endothelial growth factor signaling pathway. Hepatocellular carcinoma was induced in Sprague Dawley rats by thioacetamide. Hepatocellular carcinoma was assessed by measuring serum alpha-fetoprotein and investigating liver sections stained with hematoxylin/eosin. Hepatocellular carcinoma rats were injected with vitexicarpine (150 mg/kg) for 2 weeks. Hepatic vascular endothelial growth factor was measured by enzyme-linked immunosorbent assay. Protein and expression of hepatic phospho-Ser473-AKT (p-AKT) and phospho-Tyr419-Src (p-Src) were determined. The apoptotic pathway was evaluated by assessment of protein expression of caspase-3. Vitexicarpine increased rats' survival time and decreased serum alpha-fetoprotein as well as it ameliorated fibrosis and massive hepatic tissue breakdown. It attenuated hepatocellular carcinoma-induced protein and gene expression of vascular endothelial growth factor, p-AKT, p-Src, and caspase-3. In conclusion, this study suggests that vitexicarpine possesses both antiangiogenic and antitumor activities through inhibition of vascular endothelial growth factor, p-AKT/AKT, and p-Src with subsequent inhibition of apoptotic pathway.

The current study aims to evaluate the hepatoprotective and antitumor efficacy of doxycycline, as an matrix metalloproteases-9 (MMP-9) inhibitor, in an in vivo model of hepatocellular carcinoma (HCC). HCC was induced experimentally by thiocetamide (200 mg/kg) in rats that were treated with doxycycline (5 mg/kg for 16 weeks). Tumor severity was evaluated by measuring α-fetoprotein (AFP) levels, histopathologically by investigating liver sections stained with hematoxylin/eosin and assessing the survival rate. Liver homogenates were used for the measurements of MMP-9, fascin and hepatic heparan sulfate proteoglycan (HSPG) levels. Oxidative stress markers [malonaldehyde (MDA) and glutathione] as well as fibroblast growth factor-2 (FGF-2) gene expression were also among the assessed indicators. HCC in human and animal samples showed significant elevation in the levels of MMP-9 (231.7, 90 %), fascin (33.17, 140 %), as well as FGF-2 gene expression (342 % in animal samples; all respectively), associated with a significant decrease in hepatic HSPG level. Treatment of rats with doxycycline increased the animal survival rate (90 %) and decreased serum AFP level. Moreover, doxycycline ameliorated fibrosis and the induced massive hepatic tissue breakdown. It also restored the integrity of hepatic HSPGs and showed a magnificent inhibitory effect of tumor invasion cascade by significantly reducing the activities of MMP-9 (42 %) and fascin (50 %), as well as reducing the gene expression of FGF-2 (85.7 %). Furthermore, the antioxidant impact of doxycycline was evidenced by the significant elevation in glutathione level and depressing MDA level. To this end, doxycycline, proved promising hepatoprotective and antitumor activity and opens, thereby, a new horizon against vascular migration ability of the tumor cells.

In Egypt, hepatocellular carcinoma (HCC) was predicted to continue to rise over the next few decades causing a national problem. Meanwhile, glypican-3 (GPC3), a highly expressed glypican, has emerged as a potential target for HCC immunotherapy. Therefore, we aimed to identify the impact of blocking GPC3 on liver damage in HCC as well as a possible mechanism. Fifty four HCC patients, 20 cirrhotic patients and 10 healthy subjects were recruited. Serum levels of GPC3, sulfatase-2 (SULF-2), heparan sulfate proteoglycan (HSPG), insulin-like growth factor-II (IGF-II) were measured by ELISA. In parallel, HCC was induced in 40 male Sprague-Dawley rats in presence/absence of antiGPC-3. Liver impairment was detected by investigating liver sections stained with hematoxylin/eosin and serum α-fetoprotein (AFP). Liver homogenates of GPC3, SULF-2, and HSPG were measured by ELISA. Gene expression of caspase-3 and IGF-II were assayed by RT-PCR. HCC patients showed significant elevated serum levels of GPC3, IGF-II and SULF-2 accompanied by decreased HSPG. However, treatment of HCC rats with antiGPC-3 significantly reduced serum AFP and showed nearly normal hepatocytes. In addition, antiGPC-3 significantly reduced elevated liver homogenates protein levels of GPC3 and SULF-2 and gene expression of IGF-II and caspase-3. antiGPC-3 restored the reduced hepatic HSPG. antiGPC-3 showed anti-tumor activity as well as hepatoprotective effects. antiGPC-3-chemoprotective effect can be explained by forced reduction of IGF-II expression, restoration of HSPGs, deactivation of SULF-2 and reduction of gene expression of caspase-3. Targeting GPC3 is a promising therapeutic approach for HCC., (Copyright © 2014 Elsevier B.V. All rights reserved.)