Suberoyl bishydroxamic acid activates Notch1 signaling and suppresses tumor progression in an animal model of medullary thyroid carcinoma
Suberoyl bishydroxamic acid activates Notch1 signaling and suppresses tumor progression in an animal model of medullary thyroid carcinoma
复制标题
DOI：
10.1245/s10434-008-0006-z
复制
发表时间：
2008-09-01
影响因子：
3.7
通讯作者：
Chen, Herbert
中科院分区：
文献类型：
--
作者：
Ning, Li;Jaskula-Sztul, Renata;Chen, Herbert
背景：甲状腺髓样癌（MTC）是一种经常发生转移且治疗方法很少的神经内分泌恶性肿瘤。本研究旨在评估辛二酰基双异羟肟酸（SBHA）在MTC体内模型中的抗肿瘤作用。方法：给裸鼠注射人MTC细胞，并每隔一天注射SBHA（200 mg/kg）或载体（二甲基亚砜）生理盐水注射液，连续12天。每 4 天测量一次肿瘤，并在第 12 天收集肿瘤进行蛋白质印迹分析。结果：SBHA 治疗使治疗组的肿瘤生长平均抑制 55%（P < .05）。对 SBHA 治疗的 MTC 肿瘤的分析显示，Notch1 (NICD) 的活性形式显着增加，同时 Notch1 信号下游靶点 achaete-scute 复合体样 1 (ASCL1) 以及神经内分泌肿瘤标记物嗜铬粒蛋白 A 减少。重要的是，SBHA 治疗导致 p21(CIP1/WAF1) stop、p27(KIP1) stop 的蛋白水平增加。裂解的 caspase-9、裂解的 caspase-3 和裂解的聚 ADP-核糖聚合酶，并伴随细胞周期蛋白 D1 和细胞周期蛋白 B1 的减少，表明生长抑制是由于细胞周期停滞和细胞凋亡所致。此外，SBHA 下调细胞存活蛋白 Bcl-2 和 Bcl-X-L，但上调凋亡蛋白 Bax、Bad 和 Bmf。结论：这些结果表明 SBHA 抑制体内 MTC 生长。 SBHA 是 MTC 进一步临床前和临床研究的有希望的候选者。
Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that frequently metastasizes and has few treatments. This study was aimed at assessing the antitumor effects of suberoyl bishydroxamic acid (SBHA) in an in vivo model of MTC.Methods: Nude mice were injected with human MTC cells, and the groups were treated with SBHA (200 mg/kg) or vehicle (dimethyl sulfoxide) in saline injection every other day for 12 days. Tumors were measured every 4 days and collected at 12 days for Western blot analysis.Results: Treatment with SBHA resulted in an average 55% inhibition of tumor growth in the treatment group (P < .05). Analysis of SBHA-treated MTC tumors revealed a marked increase in the active form of Notch1 (NICD) with a concomitant decrease in achaete-scute complex-like 1 (ASCL1), a downstream target of Notch1 signaling, as well as the neuroendocrine tumor marker chromogranin A. Importantly, SBHA treatment resulted in an increase in protein levels of p21(CIP1/WAF1) stop, p27(KIP1) stop, cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase and concomitant with a decrease in cyclin D1 and cyclin B1, indicating that the growth inhibition was due to both cell cycle arrest and apoptosis. Moreover, SBHA downregulated cell survival proteins Bcl-2 and Bcl-X-L, but upregulated apoptotic proteins Bax, Bad, and Bmf.Conclusion: These results demonstrate that SBHA inhibits MTC growth in vivo. SBHA is a promising candidate for further preclinical and clinical studies in MTC.