Multiple targets modulation of Bcl-2/CD1, caspase-3 and refinement of AKT/ERK signalling by sorafenib in hepatocellular carcinoma in rats; comprehensive outlook

IF 0.7 Q4 PHARMACOLOGY & PHARMACY
M. Hamzawy, Laila A Rahsed, Sayed Mizar
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Abstract

Background Hepatocellular carcinoma (HCC) is the commonly diagnosed cancer among the three top ranked cancer induced mortality in cancer patients worldwide. A tyrosine kinase inhibitor sorafenib has been used as systemic therapy with a demonstrated survival benefit in HCC. Objectives The present work was conducted to investigate the multiple targets that may be involved in the action of sorafenib in treatment of HCC and development of drug resistance. Materials and methods Four groups of Swiss albino rats were assigned for 12 weeks treatment as the following: group (I) untreated control, group (II): rats received Diethyl Nitrosamine(DEN) (200 mg/kg, i.p)+Carbon Tetra Chloride (CCl4)(3 ml/kg, sc) every week for the first eight weeks, group (III): daily treatment with sorafenib (10 mg/kg, p.o.) for last 4 weeks, group (IV) sorafenib treatment after DEN + CCl4 treatment. Blood samples, and liver tissues were removed for collection to perform biochemical analysis (alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alpha fetoprotein (AFP), B-cell lymphoma 2 (Bcl-2), cyclin D1 (CD1), nuclear factor kappa light chain enhancer of activated B cells (NF-kB), caspase-3, and gene expression of AKT, and ERK 1/2, as well as histological examinations. Results and conclusion Administration of diethyl nitrosamine and carbon tetra chloride showed severe changes in all measured parameters and histological photomicrographs. Daily treatment with sorafenib markedly decreased B-cell lymphoma 2 (Bcl-2), cyclin D1 (CD1), nuclear factor kappa light chain enhancer of activated B cells (NF-kB) accompanied by improvement of active caspase-3. Sorafenib succeeded in restoring the gene expression of ERK 1/2 and AKT level and refinement of histological patterns in animals induced with DEN and CCL4. Sorafenib interrupts various cell communication pathways that control cancer progression, angiogenesis, and cell survival. Sorafenib regulates the AKT/ERK signaling pathway in HCC. study highlights the importance of investigating other therapeutic targets that may help combat sorafenib resistance in relation to different DNA repair mechanisms.
索拉非尼在大鼠肝细胞癌中对 Bcl-2/CD1、caspase-3 和 AKT/ERK 信号的多靶点调节;全面展望
背景 肝细胞癌(HCC)是一种常见的癌症,在全球癌症患者因癌症导致的死亡率中位居前三位。酪氨酸激酶抑制剂索拉非尼已被用作全身治疗,并已证明对 HCC 患者的生存有益。本研究旨在探讨索拉非尼治疗 HCC 时可能涉及的多个靶点以及耐药性的产生。材料和方法 将四组瑞士白化大鼠分配为以下几组,进行为期 12 周的治疗:组(I)为未治疗对照组;组(II):前八周每周接受亚硝胺二乙酯(DEN)(200 毫克/千克,静注)+四氯化 碳(CCl4)(3 毫升/千克, sc)治疗;组(III):最后四周每天接受索拉非尼(10 毫克/千克,p.o.)治疗;组(IV)在接受 DEN + CCl4 治疗后接受索拉非尼治疗。采集血样和肝组织进行生化分析(丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、甲胎蛋白(AFP)、B细胞淋巴瘤 2(Bcl-2)、细胞周期蛋白 D1(CD1)、活化 B 细胞的核因子卡巴轻链增强子(NF-kB)、Caspase-3、AKT 和 ERK 1/2的基因表达)以及组织学检查。结果和结论 施用亚硝胺二乙酯和四氯化碳会导致所有测量参数和组织学显微照片发生严重变化。索拉非尼的日常治疗显著降低了 B 细胞淋巴瘤 2(Bcl-2)、细胞周期蛋白 D1(CD1)、活化 B 细胞的核因子卡巴轻链增强子(NF-kB),同时改善了活性 caspase-3。索拉非尼成功地恢复了ERK 1/2和AKT的基因表达水平,并改善了用DEN和CCL4诱导的动物的组织学形态。索拉非尼能中断控制癌症进展、血管生成和细胞存活的各种细胞通讯途径。索拉非尼调节HCC中的AKT/ERK信号通路。该研究强调了研究其他治疗靶点的重要性,这些靶点可能有助于对抗与不同DNA修复机制有关的索拉非尼耐药性。
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来源期刊
Egyptian Pharmaceutical Journal
Egyptian Pharmaceutical Journal PHARMACOLOGY & PHARMACY-
CiteScore
1.10
自引率
0.00%
发文量
37
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