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。     

甲苯磺酸索拉非尼片的制备以及体外溶出行为考察

目的：制备甲苯磺酸索拉非尼片并考察其体外溶出行为。方法：以交联羧甲基纤维素钠为崩解剂,微晶纤维素为填充剂,十二烷基硫酸钠为增溶剂,制备本片。以f2值为考察指标,采用正交设计法筛选最优处方。结果：在不同溶出介质中,自制制剂的溶出曲线和进口制剂的体外溶出特征相似。结论：按优化的处方工艺制备的本片符合规定,可操作性强;溶出动力学特征符合一级方程。     

索拉非尼对胃癌细胞MGC80-3抑制作用实验研究

目的：探讨索拉非尼对体外培养人胃癌MGC80-3细胞增殖和凋亡的作用以及作用机制。方法采用二苯基四氮唑溴盐比色法(MTT法)检测不同浓度索拉非尼作用人胃癌MGC80-3细胞的抑制作用;AnnexinV/PI双染法观察药物处理后细胞凋亡率变化。结果索拉非尼对人胃癌MGC80-3细胞增殖具有明显抑制作用,且呈剂量和时间依赖性,与对照组比较差异有统计学意义(孕<0.05)。结论索拉非尼能够诱导细胞凋亡,并随浓度增高凋亡率增加。     

肝动脉化疗栓塞联合索拉菲尼在多发性肝细胞癌治疗中的应用研究

目的 研究肝动脉化疗栓塞(TACE)联合索拉菲尼在多发性肝细胞癌(MHCC)治疗中的应用效果.方法 选取2010年12月至2012年11月于自贡市第四人民医院接受治疗的MHCC患者148例,依据随机数字表法按1∶1的比例分为A、B两组,两组一般资料差异无统计学意义(P＞0.05).A组行单纯TACE治疗,B组行TACE联合索拉菲尼治疗.观察两组治疗前后甲胎蛋白(AFP)、高尔基体蛋白73(GP73)、铁蛋白(FER)、E-钙粘连蛋白(EC)、内皮抑素(E)、癌胚抗原(CEA)、血管内皮生长因子(VEGF)等水平、缓解率、控制率、临床疗效及不良反应.结果 治疗后B组AFP、GP73、FER、EC、E、CEA和VEGF水平均低于A组,差异有统计学意义(P＜0.05).B组缓解率、控制率均高于A组,但差异无统计学意义(P＞0.05).B组中位生存时间、总生存时间均高于A组,差异无统计学意义(P＞0.05).B组脱发、腹泻、手足反应等不良反应发生率高于A组,差异有统计学意义(P＜0.05),两组不良反应经对症处理后均缓解.结论 TACE联合索拉菲尼治疗MHCC较单纯TACE更有优势.     

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.     

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.     

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。