Biotechnology, Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt.
Anatomy Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Bioorg Chem. 2021 Nov;116:105329. doi: 10.1016/j.bioorg.2021.105329. Epub 2021 Sep 3.
There are current attempts to find a safe substitute or adjuvant for Sorafenib (Sorf), the standard treatment for advanced hepatocellular carcinoma (HCC), as it triggers very harsh side effects and drug-resistance. The therapeutic properties of Bee Venom (BV) and its active component, Melittin (Mel), make them suitable candidates as potential anti-cancer agents per-se or as adjuvants for cancer chemotherapy. Hence, this study aimed to evaluate the combining effect of BV and Mel with Sorf on HepG2 cells and to investigate their molecular mechanisms of action. Docking between Mel and different tumor-markers was performed. The cytotoxicity of BV, Mel and Sorf on HepG2 and THLE-2 cells was conducted. Combinations of BV/Sorf and Mel/Sorf were performed in non-constant ratios on HepG2. Expression of major cancer-related genes and oxidative stress status was evaluated and the cell cycle was analyzed. The computational analysis showed that Mel can bind to and inhibit XIAP, Bcl2, MDM2, CDK2 and MMP12. Single treatments of BV, Mel and Sorf on HepG2 showed lower ICthan on THLE-2. All combinations revealed a synergistic effect at a combination index (CI) < 1. Significant upregulation (p < 0.05) of p53, Bax, Cas3, Cas7 and PTEN and significant downregulation (p < 0.05) of Bcl-2, Cyclin-D1, Rac1, Nf-κB, HIF-1a, VEGF and MMP9 were observed. The oxidative stress markers including MDA, SOD, CAT and GPx showed insignificant changes, while the cell cycle was arrested at G2/M phase. In conclusion, BV and Mel have a synergistic anticancer effect with Sorf on HepG2 that may represent a new enhancing strategy for HCC treatment.
目前，人们试图寻找一种安全的替代物或佐剂来替代索拉非尼（Sorf），因为它会引发非常严重的副作用和耐药性，而索拉非尼是晚期肝细胞癌（HCC）的标准治疗药物。蜂毒（BV）及其有效成分蜂肽（Mel）的治疗特性使它们成为潜在的抗癌药物，或者作为癌症化疗的佐剂。因此，本研究旨在评估 BV 和 Mel 与 Sorf 联合对 HepG2 细胞的作用，并探讨其作用机制。进行了 Mel 与不同肿瘤标志物之间的对接。检测了 BV、Mel 和 Sorf 对 HepG2 和 THLE-2 细胞的细胞毒性。在 HepG2 上以非恒定比例进行了 BV/Sorf 和 Mel/Sorf 的组合。评估了主要癌症相关基因的表达和氧化应激状态，并分析了细胞周期。计算分析表明，Mel 可以与 XIAP、Bcl2、MDM2、CDK2 和 MMP12 结合并抑制其活性。BV、Mel 和 Sorf 对 HepG2 的单一处理显示出比 THLE-2 更低的 IC。所有组合的组合指数（CI）均<1，显示出协同作用。p53、Bax、Cas3、Cas7 和 PTEN 的表达显著上调（p<0.05），Bcl-2、Cyclin-D1、Rac1、Nf-κB、HIF-1a、VEGF 和 MMP9 的表达显著下调（p<0.05）。氧化应激标志物 MDA、SOD、CAT 和 GPx 变化不明显，细胞周期被阻滞在 G2/M 期。综上所述，BV 和 Mel 与 Sorf 对 HepG2 具有协同抗癌作用，可能代表 HCC 治疗的一种新的增强策略。
