Dong Xu , Xingzhi Feng , Yuxin Wan , Lanlan Yang , Qianling Gao , Zihuan Yang , Chang Du
{"title":"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","authors":"Dong Xu , Xingzhi Feng , Yuxin Wan , Lanlan Yang , Qianling Gao , Zihuan Yang , Chang Du","doi":"10.1016/j.smaim.2023.06.001","DOIUrl":null,"url":null,"abstract":"<div><p>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 <em>in vivo</em> evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1<sup>high</sup> 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.</p></div>","PeriodicalId":22019,"journal":{"name":"Smart Materials in Medicine","volume":"4 ","pages":"Pages 648-660"},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Curcumin nano-prodrug induces multi-phase cell cycle arrest in colorectal cancer through suppression of CDKs and specific down-regulation of PLK1\",\"authors\":\"Dong Xu , Xingzhi Feng , Yuxin Wan , Lanlan Yang , Qianling Gao , Zihuan Yang , Chang Du\",\"doi\":\"10.1016/j.smaim.2023.06.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <em>in vivo</em> evaluation using a CRC patient-derived tumor xenograft (PDX) model indicated that mCur exhibited better antitumor effects via more significant downregulation of PLK1 in PLK1<sup>high</sup> 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.</p></div>\",\"PeriodicalId\":22019,\"journal\":{\"name\":\"Smart Materials in Medicine\",\"volume\":\"4 \",\"pages\":\"Pages 648-660\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Smart Materials in Medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590183423000182\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Engineering\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Smart Materials in Medicine","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590183423000182","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Engineering","Score":null,"Total":0}
Curcumin nano-prodrug induces multi-phase cell cycle arrest in colorectal cancer through suppression of CDKs and specific down-regulation of PLK1
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.