Park Soojong, Fudhaili Ahmad, Oh Sang-Seok, Lee Ki Won, Madhi Hamadi, Kim Dong-Hee, Yoo Jiyun, Ryu Hyung Won, Park Ki-Hun, Kim Kwang Dong
Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.
Department of Orthopaedic Surgery, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
Phytomedicine. 2016 Nov 15;23(12):1462-1468. doi: 10.1016/j.phymed.2016.08.005. Epub 2016 Aug 24.
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.
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.
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.
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 G 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.
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.
构树，也被称为楮树，一直被用作传统药物来治疗多种疾病，包括眼科疾病和阳痿。然而，从构树中分离出的黄酮醇类化合物中，卡齐诺醇A（1）的生物活性尚未得到鉴定。
我们从构树中鉴定出一种抗人膀胱癌治疗的候选代谢产物，并研究其在T24和顺铂耐药的T24R2人膀胱癌细胞中细胞毒性作用的潜在分子机制。
用构树中的五种黄酮醇处理T24和T24R2细胞，并通过MTT法、细胞周期分析、线粒体膜电位和碘化丙啶染色来测定其细胞毒性作用。通过计数细胞中LC3-GFP斑点来计算自噬率。所有相关蛋白表达均通过免疫印迹法进行分析。
化合物1在人膀胱癌细胞T24和T24R2中显示出相对较高的细胞毒性，而对其他组织来源的癌细胞则不然。化合物1通过降低细胞周期蛋白D1和增加p21介导的G期阻滞显著减弱细胞生长。化合物1处理诱导的凋亡和自噬分别伴随着AKT-BAD途径和AMPK-mTOR途径的调节。
我们的结果表明，化合物1在人膀胱癌细胞中诱导细胞毒性作用，包括顺铂耐药的T24R2细胞。化合物1可能是开发有效抗人膀胱癌药物的候选物。
