Yeong-In Yang1, Ji-Hye Ahn1, Youn Seok Choi2, Jung-Hye Choi3. 1. Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, South Korea; Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul, South Korea. 2. Department of Obstetrics and Gynecology, School of Medicine, Catholic University of Daegu, Daegu, South Korea. 3. Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, South Korea; Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul, South Korea. Electronic address: jchoi@khu.ac.kr.
Abstract
OBJECTIVE: The clinical application of cisplatin is limited due to its drug resistance and side effects. We investigated the effect of a phlorotannin-rich extract from the edible brown alga Ecklonia cava (PREC) and its major phlorotannin (dieckol) on cisplatin responsiveness and side effects. METHODS: The A2780 and SKOV3 ovarian cancer cell lines and the SKOV3-bearing mouse model were used. The MTT assay was applied to assess cell viability, and the annexin V assay was employed for apoptosis analysis. Reactive oxygen species (ROS) production and protein expression were assessed by H2DCFDA staining and Western blotting, respectively. RESULTS: We found that PREC enhanced the tumor growth-inhibitory effect of cisplatin and diminished cisplatin-induced nephrotoxicity and weight loss in SKOV3-bearing mice. PREC augmented cisplatin-induced apoptosis by activating caspases in SKOV3 and A2780 ovarian cancer cells. In addition, a combination of PREC and cisplatin-induced ovarian cancer cell apoptosis by downregulating the Akt and NFκB pathways. We further demonstrated that PREC increased intracellular ROS and that antioxidants significantly attenuated Akt-NFκB activation and apoptosis in ovarian cancer cells. In contrast, PREC inhibited cisplatin-induced ROS production and cell death in normal HEK293 kidney cells. Dieckol, a major compound in PREC, significantly enhanced the inhibition of tumor growth by cisplatin with less weight loss and kidney damage in a mouse model. CONCLUSION: These data suggest that brown algae phlorotannins may improve the efficacy of platinum drugs for ovarian cancer by enhancing cancer cell apoptosis via the ROS/Akt/NFκB pathway and reduce nephrotoxicity by protecting against normal kidney cell damage.
OBJECTIVE: The clinical application of cisplatin is limited due to its drug resistance and side effects. We investigated the effect of a phlorotannin-rich extract from the edible brown alga Ecklonia cava (PREC) and its major phlorotannin (dieckol) on cisplatin responsiveness and side effects. METHODS: The A2780 and SKOV3 ovarian cancer cell lines and the SKOV3-bearing mouse model were used. The MTT assay was applied to assess cell viability, and the annexin V assay was employed for apoptosis analysis. Reactive oxygen species (ROS) production and protein expression were assessed by H2DCFDA staining and Western blotting, respectively. RESULTS: We found that PREC enhanced the tumor growth-inhibitory effect of cisplatin and diminished cisplatin-induced nephrotoxicity and weight loss in SKOV3-bearing mice. PREC augmented cisplatin-induced apoptosis by activating caspases in SKOV3 and A2780 ovarian cancer cells. In addition, a combination of PREC and cisplatin-induced ovarian cancer cell apoptosis by downregulating the Akt and NFκB pathways. We further demonstrated that PREC increased intracellular ROS and that antioxidants significantly attenuated Akt-NFκB activation and apoptosis in ovarian cancer cells. In contrast, PREC inhibited cisplatin-induced ROS production and cell death in normal HEK293 kidney cells. Dieckol, a major compound in PREC, significantly enhanced the inhibition of tumor growth by cisplatin with less weight loss and kidney damage in a mouse model. CONCLUSION: These data suggest that brown algaephlorotannins may improve the efficacy of platinum drugs for ovarian cancer by enhancing cancer cell apoptosis via the ROS/Akt/NFκB pathway and reduce nephrotoxicity by protecting against normal kidney cell damage.