Soojong Park1, Ahmad Fudhaili1, Sang-Seok Oh1, Ki Won Lee1, Hamadi Madhi1, Dong-Hee Kim2, Jiyun Yoo1, Hyung Won Ryu3, Ki-Hun Park1, Kwang Dong Kim4. 1. Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea. 2. Department of Orthopaedic Surgery, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea. 3. Natural Medicine Research Center, KRIBB, 30-Yeongudanji-ro, Ochang-eup, Cheongwon 363-883, Republic of Korea. 4. Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea; PMBBRC, Gyeongsang National University, Jinju, Republic of Korea. Electronic address: kdkim88@gnu.ac.kr.
Abstract
BACKGROUND: Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified. PURPOSE: We identified a candidate metabolite for anti-human bladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin-resistant T24R2 human bladder cancer cells. METHODS: T24 and T24R2 cells were treated with five flavonols from B. papyrifera and their cytotoxic effects were determined using MTT assay, cell cycle analysis, mitochondrial membrane potential, and propidium iodide staining. Autophagy rate was calculated by counting LC3-GFP dots in the cells. All related protein expressions were analyzed by immunoblotting. RESULTS: Compound 1 showed relatively higher cytotoxicity in the human bladder cancer cells, T24 and T24R2, rather than other tissues-originated cancer cells. Compound 1 significantly attenuated cell growth through G0/1 arrest mediated by a decrease in cyclin D1 and an increase of p21. Apoptosis and autophagy induced by compound 1 treatment was accompanied by a modulation of the AKT-BAD pathway and AMPK-mTOR pathway, respectively. CONCLUSIONS: Our results suggest that compound 1 induces cytotoxic effects in human bladder cancer cells, including the cisplatin-resistant T24R2. Compound 1 may be a candidate for the development of effective anti-cancer drug on human urinary bladder cancer.
BACKGROUND:Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified. PURPOSE: We identified a candidate metabolite for anti-humanbladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin-resistant T24R2 humanbladder cancer cells. METHODS: T24 and T24R2 cells were treated with five flavonols from B. papyrifera and their cytotoxic effects were determined using MTT assay, cell cycle analysis, mitochondrial membrane potential, and propidium iodide staining. Autophagy rate was calculated by counting LC3-GFP dots in the cells. All related protein expressions were analyzed by immunoblotting. RESULTS: Compound 1 showed relatively higher cytotoxicity in the humanbladder cancer cells, T24 and T24R2, rather than other tissues-originated cancer cells. Compound 1 significantly attenuated cell growth through G0/1 arrest mediated by a decrease in cyclin D1 and an increase of p21. Apoptosis and autophagy induced by compound 1 treatment was accompanied by a modulation of the AKT-BAD pathway and AMPK-mTOR pathway, respectively. CONCLUSIONS: Our results suggest that compound 1 induces cytotoxic effects in humanbladder cancer cells, including the cisplatin-resistant T24R2. Compound 1 may be a candidate for the development of effective anti-cancer drug on human urinary bladder cancer.
Authors: Monica Benvenuto; Loredana Albonici; Chiara Focaccetti; Sara Ciuffa; Sara Fazi; Loredana Cifaldi; Martino Tony Miele; Fernando De Maio; Ilaria Tresoldi; Vittorio Manzari; Andrea Modesti; Laura Masuelli; Roberto Bei Journal: Int J Mol Sci Date: 2020-09-10 Impact factor: 5.923