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喜树碱类似物FL118能抑制癌症生存关键基因

2012年9月22日 电 /生物谷BIOON/ --在美国,每年约有50万人死于癌症,癌症患者往往是因为癌症已经耐受现有治疗手段而最终死亡。

近日,Roswell Park癌症研究所(RPCI)的科学家取得在克服癌症耐受性方面取得了突破性进展,新的研究证实一种新的抗癌药物能抑​​制几个与癌细胞生存和繁殖能力密切相关的基因。

肿瘤学RPCI药理学和药物治疗学系副教授Fengzhi Li博士领导的研究小组证实在结构上类似依利替康和拓扑替康的喜树碱类似物FL118具有抗肿瘤作用。

肿瘤细胞耐化疗或放射治疗的主要原因是肿瘤细胞表达生存关键基因如Mcl-1,XIAP和cIAP2。Li博士和他的同事发现FL118能抑制这些基因,最终导致这些肿瘤细胞死亡。

他们还发现,FL118的存在促使癌症细胞死亡独立于肿瘤抑制基因p53,我们的研究表明FL118可能会成为早期和晚期癌、转移性或非转移性癌症的有效控制药物。

研究人员还需要确定FL118的生化指标以及药代动力学和毒理学信息才进入临床研究,但这些令人信服的临床前研究结果让相关研究人员受到莫大的鼓舞。(生物谷:Bioon.com)

A Novel Small Molecule FL118 That Selectively Inhibits Survivin, Mcl-1, XIAP and cIAP2 in a p53-Independent Manner, Shows Superior Antitumor Activity

Xiang Ling1#, Shousong Cao1,2#, Qiuying Cheng1, James T. Keefe1, Youcef M. Rustum1,3, Fengzhi Li1,3*

Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 μM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118’s effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials.

关键词:喜树碱,FL118,癌症,基因

信息来源:生物谷

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