Sorafenib,rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells

Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-galactosidase staining (SA-β-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy.     

Current status of first-line therapy,anti-angiogenic therapy and its combinations of other agents for unresectable hepatocellular carcinoma

Globally, hepatocellular carcinoma (HCC) is a frequently diagnosed malignancy with rapidly increasing incidence and mortality rates. Unfortunately, many of these patients are diagnosed in the advanced stages when locoregional treatments are not appropriate. Before 2008, no effective drug treatments existed to prolong survival, until the breakthrough multi-tyrosine kinase inhibitor (TKI) sorafenib was developed. It remained the standard treatment option for advanced HCC for 10 years, with a battery of other candidate drugs in clinical trials failing to produce similar efficacy results. In 2018, the REFLECT trial introduced another multi-TKI, lenvatinib, which has non-inferior overall survival compared with sorafenib. Thus, offering patients and their treating physicians two effective treatment options. Recently, immunotherapy-based drugs, such as atezolizumab and bevacizumab, have shown promising results in patients with unresectable HCC. This review summarizes clinical trial and real-world data studies of sorafenib and lenvatinib in patients with unresectable HCC. We offer guidance on the optimal choice between the two treatments and discuss the potential of immunotherapy-based combination; when more data become available, this will likely make the choice between sorafenib and lenvatinib somewhat obsolete.     

益气化瘀解毒方对MRP、GST-π和Topo Ⅱ基因在Sorafenib获得性耐药人肝癌QGY7702细胞表达的干预研究

目的探讨益气化瘀解毒方干预后对Sorafenib获得性耐药人肝癌QGY7702细胞(QGY7702/Sora)增殖及MRP、GST-π和Topo Ⅱ基因表达的影响。方法培养QGY7702/Sora细胞和QGY7702细胞,利用Cell Counting Kit-8(CCK-8)法检测Sorafenib对细胞的半数抑制率浓度(IC50值),计算耐药指数RI;观察益气化瘀解毒方对耐药细胞的增殖影响;采用荧光定量PCR检测药物干预前后2种细胞中MRP、GST-π和Topo Ⅱ基因表达水平。结果亲本细胞和耐药细胞Sorafenib的IC50值分别为(7.993±0.522)μmol/L和(19.651±1.216)μmol/L,RI约为2.5。益气化瘀解毒方可抑制耐药细胞的增殖活性。2种细胞的MRP、GST-π、Topo Ⅱ表达量无明显差异(P>0.05)。Sorafenib组可促进耐药细胞MRP 、GST-π基因的过表达(P<0.05),益气化瘀解毒方组可抑制GST-π基因的过表达(P<0.01),且联合Sorafenib可显著提高Topo Ⅱ基因的表达量(P<0.01)。结论 QGY7702/Sora细胞MRP、GST-π和Topo Ⅱ的表达水平与亲本细胞无显著差异。耐药细胞对Sorafenib敏感性降低与MRP、GST-π过表达相关,而益气化瘀解毒方拮抗Sorafenib耐药与抑制GST-π过表达相关。     

Sorafenib in hepatocellular carcinoma – a post marketing evaluation

Background: Sorafenib is an orally active multikinase inhibitor licensed for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Patients and methods: The web-based registry, used for appraisal on new drugs, allows developing the observational prospective analysis of innovative drug therapies. To establish clinical impact of Sorafenib, institutional data were collected prospectively through the registry.

Results: A total of 81 patients treated with Sorafenib were reviewed (median age = 65 years) and the follow-up duration was 30 months. Every patient was checked for length of treatment, toxicity and outcomes. Based on the study sample, the median time to progression was 3 months and median overall survival was 8 months. We found 52% progressions at first evaluation and the disease control rate was 32%.

Conclusion: Our data from real life practice showed that the clinical benefit of Sorafenib in unresectable HCC was gained in selected responder patients.     

Sorafenib potentiates ABT-737-induced apoptosis in human oral cancer cells

ObjectiveThe mimetic BH3 ABT-737, a potent inhibitor of anti-apoptotic Bcl-2 family proteins, has potential as anti-cancer drug in many cancers. Recently, patients treated with ABT-737 have developed drug tolerance during cancer therapy. Therefore, we examined whether ABT-737 is effective in killing MC-3 and HSC-3 human oral cancer cells either alone or in combination with the oncogenic kinase inhibitor, sorafenib.DesignThe potentiating activities of sorafenib in ABT-737-induced apoptosis were determined using trypan blue exclusion assay, DAPI staining, cell viability assay and Western blot analysis.ResultsCombined use of ABT-737 and sorafenib synergistically suppressed cell viability and induced apoptosis compared with either compound individually. The combination of ABT-737 and sorafenib altered only Bax and Bak proteins and their activations, resulting in mitochondrial translocation of Bax from the cytosol. Additionally, combination treatment-mediated apoptosis may be correlated with ERK and STAT3 pathways.ConclusionsThese results suggest that sorafenib may effectively overcome ABT-737 resistance to apoptotic cell death, which can be a new potential chemotherapeutic strategy against human oral cancer.     

Hepatocellular Carcinoma and Liver Transplantation: State of the Art

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide.With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor (“seed”) and the damaged-hepatic tissue (“soil”) where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria.However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib.Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.     

Anti-angiogenic treatment in breast cancer: Facts,successes, failures and future perspectives

Angiogenesis is one of the hallmarks of cancer and a crucial requisite in the development of tumors. Interrupting this process by blocking the vascular endothelial growth factor (VEGF) with the monoclonal antibody bevacizumab has been considered a possible breakthrough in the treatment of various types of cancer, especially for advanced disease. However in breast cancer, studies have shown ambivalent results causing debate about the value of this drug. In this article, we review the evidence for anti-angiogenic treatment options for breast cancer, as well as discuss the possible factors limiting the effectiveness of anti-angiogenic agents and offer a recommendation regarding the future research on these therapies for the treatment of breast cancer.     

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience

BackgroundAccording to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high economic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib.MethodsHCC patients treated at Ain Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinicopathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model.Results41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1 = 7.01 months and for ECOG 2 = 3.03 months), Child–Pugh status (median OS for child A = 12.04 months and for child B = 5.23 months), and median baseline levels of alpha-fetoprotein.ConclusionsIn limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.     

索拉菲尼治疗进展期原发性肝癌患者有效性及安全性研究*

目的 探讨应用索拉菲尼治疗进展期原发性肝癌(aPLC)患者的有效性和安全性。方法 2013年4月~2016年12月我科诊治的aPLC患者82例,采用随机数字表法分为两组,每组41例。两组均给予射频消融术（RFA）治疗,观察组患者在RFA前后接受索拉菲尼治疗,观察12 w。采用ELISA法检测血清碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）。结果 2例观察组患者被剔除,3例对照组患者失访;在治疗12 w末,观察组疾病控制率为61.5%,与对照组的52.6%比,差异无统计学意义（P>0.05）,但观察组肿瘤客观有效率为48.7%,显著高于对照组的26.3%,差异有统计学意义（P<0.05）;观察组血清AFP、bFGF和VEGF水平分别为（184.7±10.5）μg/L、（3.8±1.3） pg/mL和（172.3±25.4） pg/mL,均显著低于对照组的（213.6±11.6） μg/L、（6.4±2.0） pg/mL和（210.5±28.3） pg/mL,差异有统计学意义（P<0.05）;观察组中位无进展生存期（PFS）为10.2个月（95%CI为7.4~11.5）,对照组为7.9个月（95%CI为 6.0~10.1）,经Log-rank检验显示两组差异有统计学意义（P<0.05）;观察组在服药过程中手足综合征、皮疹、白细胞减少、口腔黏膜炎、脱发和肝功能异常发生率分别为43.6%、25.6%、17.9%、20.5%、25.6%和23.1%,显著高于对照组的0.0%、2.6%、0.0%、0.0%、0.0%和5.3%,差异有统计学意义（P<0.05）。结论 索拉菲尼可控制aPLC患者实体瘤扩散,延长无进展生存期,但索拉菲尼可引起多种不良反应,在用药过程中应注意观察并及时采取相应处理措施,以防止发生严重不良反应。