Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr-El-Ainy Street, Cairo 11562, Egypt.
Pathol Res Pract. 2024 Oct;262:155520. doi: 10.1016/j.prp.2024.155520. Epub 2024 Aug 22.
Carcinoma of the colon and rectum, also known as colorectal cancer, ranks as the third most frequently diagnosed malignancy globally. Sorafenib exhibits broad-spectrum antitumor activity against Raf, VEGF, and PDGF pathways in hepatocellular, thyroid, and renal cancers, but faces resistance in colorectal malignancies. 6-Shogaol, a prominent natural compound found in Zingiberaceae, exhibits antioxidant, anti-inflammatory, anticancer, and antiemetic properties. We investigated the influence of 6-shogaol on sorafenib's cytotoxic profile against colorectal cancer cell lines (HT-29, HCT-116, CaCo-2, and LS174T) through its effects on cellular accumulation and metabolism. Cytotoxicity was assessed using the sulpharodamine B assay, caspase-3 and c-PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity. 6-Shogoal showed considerable cytotoxicity with decreased IC in colorectal cancer cell lines. Combining sorafenib and 6-shogaol increased c-PARP and pro-caspase-3 concentrations in HCT-116 cells compared to sorafenib alone. In combination, pro-caspase-3 concentrations were decreased in CaCo-2 cells compared to alone. Sorafenib combinations with 6-shogaol showed a significant drop in cell cycle distribution from 16.96±1.10 % to 9.16±1.85 %, respectively. At 100 µM, sorafenib and 6-shogaol showed potent and significant activity with intra-cellular rhodamine concentration on P-gp efflux activity in CRC cell lines. In conclusion, 6-shogaol substantially improved the cytotoxic profile of sorafenib by affecting its cellular uptake and metabolism. Future research should focus on dosage optimization and formulation and evaluate the efficacy and safety of the combination in animal models with colorectal cancer.
结肠直肠癌，也称为结直肠癌，是全球第三大常见的恶性肿瘤。索拉非尼在肝癌、甲状腺癌和肾癌中对 Raf、VEGF 和 PDGF 途径具有广谱抗肿瘤活性，但在结直肠癌中存在耐药性。6-姜烯酚是姜科植物中的一种重要天然化合物，具有抗氧化、抗炎、抗癌和止吐作用。我们研究了 6-姜烯酚对索拉非尼细胞内积累和代谢的影响，及其对结直肠癌细胞系（HT-29、HCT-116、CaCo-2 和 LS174T）的细胞毒性谱的影响。通过使用磺酰罗丹明 B 测定法、caspase-3 和 c-PARP 裂解、细胞周期分布分析和 P-gp 外排活性来评估细胞毒性。6-姜烯酚在结直肠癌细胞系中表现出相当大的细胞毒性，IC 降低。与单独使用索拉非尼相比，索拉非尼和 6-姜烯酚联合使用增加了 HCT-116 细胞中的 c-PARP 和 pro-caspase-3 浓度。联合使用时，与单独使用相比，CaCo-2 细胞中的 pro-caspase-3 浓度降低。与单独使用相比，索拉非尼与 6-姜烯酚联合使用时，细胞周期分布从 16.96±1.10 %显著下降至 9.16±1.85 %。在 100 µM 时，索拉非尼和 6-姜烯酚对 CRC 细胞系中的 P-gp 外排活性具有显著的细胞内罗丹明浓度和强大的活性。总之，6-姜烯酚通过影响其细胞摄取和代谢，显著改善了索拉非尼的细胞毒性谱。未来的研究应侧重于剂量优化和制剂，并在结直肠癌动物模型中评估联合用药的疗效和安全性。
