Al-Abd Ahmed M, Al-Abbasi Fahad A, Asaad Gihan F, Abdel-Naim Ashraf B
Pharmacology and Toxicology Department, Faculty of Pharmkacy, King Abdulaziz University, Jeddah, Saudi Arabia; Pharmacology Department, Medical division, National Research Center, Dokki, 12622 Giza, Egypt.
Eur J Pharmacol. 2013 Oct 15;718(1-3):361-9. doi: 10.1016/j.ejphar.2013.08.009. Epub 2013 Sep 7.
The use of adjuvant therapies in cancer treatment is rationalized by potentiating the efficacy and/or protecting from the major side effects of chemotherapeutics. Didox, besides its antioxidant properties, is an inhibitor for DNA synthesis and repair which might recommend its use as adjuvant therapy. Herein, we have studied the effect of didox in potentiating the efficacy of doxorubicin (DOX) against liver cancer cells and protecting from its dose-limiting cardiotoxic effects. Didox combination with DOX significantly decreased in the IC50 of DOX to half its original value in Huh7 and HepG2 liver cancer cell lines. The calculated combination index (CI-value) indicated additive type of drug interaction (CI-value ranged from 0.81 to 0.9). Both didox and DOX significantly blocked the cell cycle in S-phase and their combination significantly increased cell cycle blockade. Also, didox combination significantly increase the caspase-3 level compared to DOX treatment alone. On the other hand, didox (150 mg/kg daily) significantly protected the cardiomyocyte membrane integrity and decreased the intra-cardiac oxidative stress induced by DOX treatment (15 mg/kg). This protective effect was reflected in reverting the cardiomegaly and cardio-pathological features induced by DOX treatment. Also didox prolonged the median survival time of mice treated with DOX and decreased the mortality risk by 3.7 folds. In conclusion, didox significantly potentiated the cytotoxicity of DOX in liver cancer cells and protected from its cardiotoxicity.
在癌症治疗中使用辅助疗法的合理性在于增强化疗药物的疗效和/或预防其主要副作用。除了具有抗氧化特性外，双脱氧胸苷（Didox）还是一种DNA合成和修复抑制剂，这可能使其适合用作辅助疗法。在此，我们研究了Didox增强阿霉素（DOX）对肝癌细胞的疗效以及预防其剂量限制性心脏毒性作用的效果。Didox与DOX联合使用可使DOX在Huh7和HepG2肝癌细胞系中的半数抑制浓度（IC50）显著降低至其原始值的一半。计算得出的联合指数（CI值）表明药物相互作用为相加类型（CI值范围为0.81至0.9）。Didox和DOX均显著阻断细胞周期于S期，二者联合使用则显著增强细胞周期阻滞。此外，与单独使用DOX治疗相比，Didox联合使用显著提高了半胱天冬酶-3水平。另一方面，Didox（每日150 mg/kg）显著保护心肌细胞膜完整性，并降低了DOX治疗（15 mg/kg）诱导的心脏内氧化应激。这种保护作用体现在逆转DOX治疗引起的心脏肥大和心脏病理特征方面。此外，Didox延长了接受DOX治疗小鼠的中位生存时间，并将死亡风险降低了3.7倍。总之，Didox显著增强了DOX对肝癌细胞的细胞毒性，并预防了其心脏毒性。
