Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia ; National Cancer Institute, Cairo University, Cairo, Egypt.
Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia ; Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
Cancer Cell Int. 2013 May 28;13:52. doi: 10.1186/1475-2867-13-52. eCollection 2013.
Doxorubicin (DOX), an anthracycline antibiotic is one of the most effective anticancer drug used in the treatment of variety of cancers .Its use is limited by its cardiotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of DOX and at the same time its protective effect against DOX-induced cardiotoxicity in rats.
Ehrlich ascites carcinoma bearing mice were used in this study. Percent survival of tumor bearing mice was used for determination of the Cytotoxic activity of DOX in presence and absence of RSVL. Uptake and cell cycle effect of DOX in tumor cells in the presence of RSVL was also determined. Histopatholgical examination of heart tissues after DOX and/or RSVL therapy was also investigated.
DOX at a dose level of 15 mg/kg increased the mean survival time of tumor bearing mice to 21 days compared with 15 days for non tumor-bearing control mice. Administration of RSVL at a dose level of 10 mg/kg simultaneously with DOX increased the mean survival time to 30 days with 70% survival of the tumor-bearing animals. RSVL increased the intracellular level of DOX and there was a strong correlation between the high cellular level of DOX and its cytotoxic activity. Moreover, RSVL treatment showed 4.8 fold inhibition in proliferation index of cells treated with DOX. Histopathological analysis of rat heart tissue after a single dose of DOX (20 mg/kg) showed myocytolysis with congestion of blood vessels, cytoplasmic vacuolization and fragmentation. Concomitant treatment with RSVL, fragmentation of the muscle fiber revealed normal muscle fiber.
This study suggests that RSVL could increase the cytotoxic activity of DOX and at the same time protect against its cardiotoxicity.
多柔比星（DOX）是一种蒽环类抗生素，是治疗多种癌症最有效的抗癌药物之一。其应用受到其心脏毒性的限制。本研究旨在评估天然产物白藜芦醇（RSVL）对乳腺癌（艾氏腹水癌）对 DOX 作用的敏感性的作用，同时评估其对大鼠 DOX 诱导的心脏毒性的保护作用。
本研究使用艾氏腹水癌荷瘤小鼠。肿瘤荷瘤小鼠的存活率用于确定 DOX 在存在和不存在 RSVL 时的细胞毒性作用。还测定了 RSVL 存在时肿瘤细胞中 DOX 的摄取和细胞周期效应。还研究了 DOX 和/或 RSVL 治疗后心脏组织的组织病理学检查。
DOX 剂量为 15mg/kg 时，与非荷瘤对照小鼠的 15 天相比，增加了荷瘤小鼠的平均存活时间至 21 天。RSVL 剂量为 10mg/kg 与 DOX 同时给药时，将平均存活时间增加至 30 天，荷瘤动物的存活率为 70%。RSVL 增加了 DOX 的细胞内水平，并且细胞内高水平的 DOX 与其细胞毒性活性之间存在很强的相关性。此外，RSVL 处理显示出 DOX 处理的细胞增殖指数降低了 4.8 倍。单次给予 DOX（20mg/kg）后大鼠心脏组织的组织学分析显示肌溶解伴血管充血、细胞质空泡化和碎裂。同时用 RSVL 治疗，肌纤维碎裂显示出正常的肌纤维。
本研究表明，RSVL 可以增加 DOX 的细胞毒性作用，同时可以预防其心脏毒性。
