Carlson Lisa Janssen, Cote Brianna, Alani Adam Wg, Rao Deepa A
School of Pharmacy, Pacific University, Hillsboro, Oregon, 97123.
J Pharm Sci. 2014 Aug;103(8):2315-22. doi: 10.1002/jps.24042. Epub 2014 Jun 9.
Resveratrol (RES) and curcumin (CUR) have free radical scavenging ability and potential chemosensitizing effects. Doxorubicin hydrochloride (DH) is a potent chemotherapeutic with severe cardiotoxicity. We hypothesize that RES and CUR co-loaded in Pluronic(®) micelles and co-administered with DH will result in cardioprotective effects while maintaining/improving DH anti-proliferative effect in vitro. RES-CUR at a molar ratio of 5:1 in F127 micelles (mRC) were prepared and characterized for size, drug loading, and release. In vitro cell viability and apoptosis assays in ovarian cancer cells (SKOV-3) and cardiomyocytes (H9C2) with either individual drugs or RES-CUR or mRC in combination with DH were conducted. Combination index (CI) analysis was performed to determine combination effects. Reactive oxygen species (ROS) were quantified in H9C2 for DH, and combinations. The mRC solubilized 2.96 and 0.97 mg/mL of RES and CUR, respectively. Cell viability and CI studies indicated that the combinations were synergistic in SKOV-3 and antagonistic in H9C2 cells. Caspase 3/7 activity in combination treatments was lower than with DH alone in both cell lines. ROS activity was restored to baseline in H9C2 cells in the micelle combination groups. Co-administration of mRC with DH in vitro mitigates DH-induced cardiotoxicity through reduction in apoptosis and ROS while improving DH potency in ovarian cancer cells.
白藜芦醇（RES）和姜黄素（CUR）具有自由基清除能力和潜在的化学增敏作用。盐酸多柔比星（DH）是一种强效化疗药物，但具有严重的心脏毒性。我们假设，负载于普朗尼克（®）胶束中的RES和CUR与DH联合给药，将产生心脏保护作用，同时在体外维持/提高DH的抗增殖作用。制备了F127胶束中摩尔比为5:1的RES-CUR（mRC），并对其粒径、载药量和释放情况进行了表征。对卵巢癌细胞（SKOV-3）和心肌细胞（H9C2）进行了体外细胞活力和凋亡检测，检测药物分别为单独的RES、CUR、mRC以及它们与DH的组合。进行组合指数（CI）分析以确定联合效应。对H9C2细胞中DH及其组合的活性氧（ROS）进行了定量分析。mRC分别溶解了2.96 mg/mL的RES和0.97 mg/mL的CUR。细胞活力和CI研究表明，这些组合在SKOV-3细胞中具有协同作用，而在H9C2细胞中具有拮抗作用。在两种细胞系中，联合治疗组的半胱天冬酶3/7活性均低于单独使用DH组。胶束组合组H9C2细胞中的ROS活性恢复到了基线水平。体外将mRC与DH联合给药可减轻DH诱导的心脏毒性，其机制是减少细胞凋亡和ROS，同时提高DH对卵巢癌细胞的效力。
