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Therapeutic potential of snake venom, l-amino oxidase and sorafenib in hepatocellular carcinoma
Molecular & Cellular Toxicology ( IF 1.7 ) Pub Date : 2021-07-06 , DOI: 10.1007/s13273-021-00151-8
Dalia H. Mahfouz 1 , Ghada H. Mansour 1 , Ismail A. Abdelhamid 1 , Mohammed A. El-Magd 2 , Abdel Hady Abdel Wahab 3 , Emad Elzayat 4
Affiliation  

Background

Sorafenib (SOR) is the only approved molecular targeted agent for the treatment of hepatocellular carcinoma (HCC), however, its use is delayed by the recently articulated safety concerns.

Objective

The present study aimed to test the hypothesis that combining snake venoms (SVs) or its ingredient l-amino acid oxidase (LAAO) could synergistically enhance the anti-proliferative effects of SOR at low doses on liver cancer cells (HepG2) versus normal liver cells (THLE2).

Methods

The cytotoxic effects were measured on HepG2 and THLE-2 using MTT assay. Gene expression for apoptotic, inflammatory, antioxidant and cell cycle regulator genes was detected by real-time PCR. The number of cells in each cell cycle phase was determined by flow cytometry.

Results

SV, LAAO, and SOR exhibited higher cytotoxicity on HepG2 cells than THLE2 cells with the 2 combinations (2 LAAO + 3/4 SOR and 3 LAAO + 3/4 SOR) showed a potent synergistic anti-tumor effect on HepG2 while being safer on THLE-2. These 2 combinations significantly elevated the expression of apoptotic (Bax, caspase 3, 8, 9, p21), inflammatory (IL6, IL1β), and antioxidant (Nrf2 and HO-1) genes, and significantly decreased the expression of the anti-apoptotic Bcl2 and DNA topoisomerase 2-binding protein 1 (Topbp1) genes relative to the single treatment. Besides, there were a significant increase in MDA and SOD but a significant decrease in GPx and CAT activity in combined and single treatments with SOR versus the untreated control. The combined therapy also arrested HepG2 in the G2/M phase.

Conclusion

Our results suggest a novel synergistic, selective, inflammatory, and anti-proliferative effect of SV or LAAO with SOR on HepG2 cells. These 2 novel combinations could serve as a potential tool for the development of a novel therapeutic approach against HCC.



中文翻译:

蛇毒、L-氨基氧化酶和索拉非尼在肝细胞癌中的治疗潜力

背景

索拉非尼 (SOR) 是唯一获批用于治疗肝细胞癌 (HCC) 的分子靶向药物,但由于最近提出的安全问题,其使用被推迟。

客观的

本研究旨在检验组合蛇毒 (SV) 或其成分l-氨基酸氧化酶 (LAAO) 可以协同增强低剂量 SOR 对肝癌细胞 (HepG2) 与正常肝细胞的抗增殖作用的假设。(THLE2)。

方法

使用MTT测定法测量对HepG2和THLE-2的细胞毒性作用。通过实时 PCR 检测凋亡、炎症、抗氧化和细胞周期调节基因的基因表达。通过流式细胞术测定每个细胞周期阶段的细胞数。

结果

SV、LAAO 和 SOR 对 HepG2 细胞的细胞毒性高于 THLE2 细胞,2 种组合(2 LAAO + 3/4 SOR 和 3 LAAO + 3/4 SOR)对 HepG2 显示出有效的协同抗肿瘤作用,同时对 HepG2 更安全。 THLE-2。这2种组合显着提高了凋亡(Bax、caspase 3、8、9p21)、炎症(IL6、IL1β)和抗氧化(Nrf2HO-1)基因的表达,并显着降低了抗凋亡基因的表达。Bcl2和 DNA 拓扑异构酶 2 结合蛋白 1 ( Topbp1) 基因相对于单一治疗。此外,与未处理的对照相比,在使用 SOR 的组合和单一处理中,MDA 和 SOD 显着增加,但 GPx 和 CAT 活性显着降低。联合疗法还在 G2/M 期阻止了 HepG2。

结论

我们的结果表明 SV 或 LAAO 与 SOR 对 HepG2 细胞具有新的协同、选择性、炎症和抗增殖作用。这 2 种新型组合可作为开发针对 HCC 的新型治疗方法的潜在工具。

更新日期:2021-07-06
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