PDF(Pubmed)
Abstract：
Daunorubicin, also known as daunomycin, is a DNA‑targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA‑approved drug library, it was found that daunorubicin suppresses GLI‑dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the β‑TrCP‑mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY‑cyclopamine, a well‑known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin\'s anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.
摘要：
柔红霉素,也被称为道诺霉素，是一种DNA靶向抗癌药物，用作化疗，主要针对白血病患者。它还被证明在实体瘤的单一疗法或联合疗法中具有抗癌作用，但目前尚未在结直肠癌（CRC）中进行充分研究。在本研究中,使用FDA批准的药物库进行筛查，发现柔红霉素抑制GLI依赖性荧光素酶报告活性。柔红霉素也增加p53水平，这有助于GLI1抑制和细胞凋亡。目前的详细研究表明，柔红霉素促进了β-TrCP介导的GLI1的泛素化和蛋白酶体降解。此外，使用BODIPY-环巴明的竞争实验，一种著名的Smo抑制剂,提示柔红霉素不与HCT116细胞中的Smo结合。施用柔红霉素（2mg/kg，ip,qod,15天）进入HCT116异种移植小鼠，极大地抑制了肿瘤进展和肿瘤组织中的GLI1水平。一起来看,目前的结果表明，柔红霉素抑制CRC中的经典Hedgehog途径。最终,本研究揭示了柔红霉素抗癌作用的新机制，为拓展柔红霉素的临床应用提供了理论基础。
