Curcumin nano-prodrug induces multi-phase cell cycle arrest in colorectal cancer through suppression of CDKs and specific down-regulation of PLK1

Q1 Engineering Smart Materials in Medicine Pub Date : 2023-01-01 DOI:10.1016/j.smaim.2023.06.001
Dong Xu , Xingzhi Feng , Yuxin Wan , Lanlan Yang , Qianling Gao , Zihuan Yang , Chang Du
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引用次数: 1

Abstract

Aberrant activation of cell cycle proteins leads to tumor progression in most cancer types. While 5-fluorouracil (5-Fu)-based chemotherapy remains the first-line treatment strategy for colorectal cancer (CRC), more than 40% of patients with advanced CRC do not benefit from the regimen. Herein, a chemically modified curcumin (mCur) was developed to explore its curative effect on CRC and reveal its potential role in cell cycle regulation. Amphiphilic mCur could self-assemble into positively charged nano-micelles, hence facilitating high cellular uptake and anticancer activity. Multi-phase cell cycle arrest, induced by both mCur and Cur, was first observed in HCT 116 ​cells. This phenomenon was mainly attributed to the Cur/mCur mediated downregulation of cyclin-dependent kinases (CDKs) and their direct interactions. Moreover, mCur and Cur treatments generated distinct phenotypic signatures. In particular, mCur induced distinct dynamic fluctuations in cell cycle and a relatively higher proportion of cells in the G2/M phase than Cur, and specifically triggered the impaired expression of polo-like kinase 1 (PLK1). An in vivo evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1high PDX, with no obvious systemic toxicity. Collectively, our study revealed a unique multi-phase cell cycle arrest effect of Cur-based antitumor agents and highlighted the potential of mCur as a PLK1-targeted inhibitor for CRC therapy.

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姜黄素纳米前药通过抑制CDKs和特异性下调PLK1诱导结直肠癌多相细胞周期阻滞
细胞周期蛋白的异常激活导致大多数癌症类型的肿瘤进展。虽然以5-氟尿嘧啶(5-Fu)为基础的化疗仍然是癌症(CRC)的一线治疗策略,但超过40%的晚期CRC患者没有从该方案中获益。本文开发了一种化学修饰的姜黄素(mCur),以探索其对CRC的疗效,并揭示其在细胞周期调控中的潜在作用。两亲性mCur可以自组装成带正电的纳米胶束,从而促进细胞的高摄取和抗癌活性。mCur和Cur诱导的多相细胞周期阻滞首次在HCT 116中观察到​细胞。这种现象主要归因于Cur/mCur介导的细胞周期蛋白依赖性激酶(CDKs)的下调及其直接相互作用。此外,mCur和Cur处理产生了不同的表型特征。特别是,mCur诱导了细胞周期的明显动态波动,G2/M期的细胞比例相对高于Cur,并特别触发了polo-like激酶1(PLK1)的表达受损。使用CRC患者来源的肿瘤异种移植物(PDX)模型进行的体内评估表明,mCur通过在PLK1高PDX中更显著地下调PLK1而表现出更好的抗肿瘤作用,没有明显的全身毒性。总之,我们的研究揭示了基于Cur的抗肿瘤药物独特的多期细胞周期阻滞作用,并强调了mCur作为PLK1靶向抑制剂用于CRC治疗的潜力。
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来源期刊
Smart Materials in Medicine
Smart Materials in Medicine Engineering-Biomedical Engineering
CiteScore
14.00
自引率
0.00%
发文量
41
审稿时长
48 days
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