A novel small-molecule YLT256 inhibits proliferation and induces apoptosis both in vitro and in vivo in solid tumors

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• 作者：Hongxia Deng¹ ; Jun Zeng¹ ; Yongxia Zhu ; Tinghong Ye ; Yong Xia ; Yaojie Shi ; Ningyu Wang ; Lidan Zhang ; Xuejiao Song ; Weiqiong Zuo ; Tiantao Gao ; Luoting Yu ; ^{yuluot@scu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Bcl-2 ; B-cell lymphoma 2 ; Bak ; Bcl-2 antagonist/killer-1 ; ΔΨm ; mitochondrial membrane potential ; ROS ; reactive oxygen species ; MTT ; 3-(4 ; 5-dimethyl-2-thiazolyl)-2 ; 5-di-phenyl-2H-tetrazoliumbromide ; PI ; propidium iodide ; Rh123 ; rhodamine-123 ; DCFA-DA ; 2&prime ; 7&prime ; -dichlorofluoresein diacetate ; DMSO ; dimethyl sulfoxide ; FBS ; fetal bovine serum ; DMEM ; Dulbecco&rsquo ; s modified Eagle medium ; FCM ; flow cytometry ; IC50 ; median inhibitory concentration ; RIPA ; radio-immunoprecipitation assay ; SDS-PA
• 刊名：Biomedicine & Pharmacotherapy
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：81
• 期：Complete
• 页码：482-490
• 全文大小：3520 K

文摘

Pancreatic carcinoma is a still unsolved health problem all over the world with poor prognosis and high mortality rate. YLT256, a novel synthesized chemical small inhibitor, displays potent antineoplastic activities via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT256 showed growth inhibition against a broad spectrum of human cancer cell lines and pancreatic cancer cell line BxPc-3 was the most sensitive with an IC₅₀ of 0.42 μM. We also found YLT256 could induce apoptosis of BxPc-3 cells in a dose-dependent manner. Western blot analysis revealed that the occurrence of its apoptosis was associated with activation of caspases-3 and -9, up-regulation of pro-apoptotic Bak, and down-regulation of anti-apoptotic Bcl-2. Moreover, YLT256-treated resulted in changes of mitochondrial membrane potential (Δψm), and generation of reactive oxygen species (ROS). Furthermore, our data also revealed that YLT256 suppressed the growth of established tumor-bearing xenograft models without obvious side effects. Immunohistochemical analyses and TUNEL assay revealed an increase in cleaved caspase-3-positive cells and TUNEL-positive cells, a decrease in Ki67-positive cells upon YLT256. Together, all the results of present study provided evidence demonstrating that YLT256 could be a promising potential drug candidate for pancreatic cancer therapy.