Sam Khan , Ankur Karmokar , Lynne Howells , Robert G. Britton , Emma Parrott , Raquel Palacios-Gallego , Cristina Tufarelli , Hong Cai , Jennifer Higgins , Nicolas Sylvius , Kevin West , Angus McGregor , David Moore , Selena G. Burgess , Mark W. Richards , Anja Winter , Zahirah Sidat , Nalini Foreman , Sanne T. Hoorn , Louis Vermeulen , Karen Brown
{"title":"An old spice with new tricks: Curcumin targets adenoma and colorectal cancer stem-like cells associated with poor survival outcomes","authors":"Sam Khan , Ankur Karmokar , Lynne Howells , Robert G. Britton , Emma Parrott , Raquel Palacios-Gallego , Cristina Tufarelli , Hong Cai , Jennifer Higgins , Nicolas Sylvius , Kevin West , Angus McGregor , David Moore , Selena G. Burgess , Mark W. Richards , Anja Winter , Zahirah Sidat , Nalini Foreman , Sanne T. Hoorn , Louis Vermeulen , Karen Brown","doi":"10.1016/j.canlet.2025.217885","DOIUrl":null,"url":null,"abstract":"<div><div>The cost of cancer care globally is unsustainable and strategies to reduce the mounting burden of cancer are urgently needed. One approach is the use of preventive therapies to reduce cancer risk; dietary-derived compounds with good safety profiles represent a promising source of potential candidates but translating encouraging preclinical data to successful trials presents significant challenges. Development of curcumin, from the spice turmeric, as a preventive therapy for colorectal cancer (CRC) is hindered by poor understanding of its mechanism of action. Using patient derived xenografts and <em>ex-vivo</em> 3D-models exposed to clinically achievable curcumin concentrations, we found that it targets proliferating cancer stem-like cells (CSCs) within premalignant adenoma and early-stage cancer tissues, with broad spectrum activity across all molecular subtypes. Transcriptomics analysis revealed that curcumin pushes CSCs towards differentiation over self-renewal, thereby inhibiting tumour development. Evidence suggests these effects involve direct protein binding of curcumin to NANOG, a master regulator of CRC CSCs, and impairment of its transcriptional activity via direct interference with NANOG-DNA binding. Furthermore, curcumin decreased the proportion of proliferating CSCs, defined by NANOG/Ki67 co-expression in patient derived explants and individuals with tumours containing a small fraction of these cells had greatly improved progression-free survival compared to those in the highest quartile for expression. The use of curcumin to minimise this cellular population may yield significant benefit and its clinical evaluation is warranted. Overall, this study provides crucial mechanistic insight, identifying patient populations likely to benefit from curcumin for prevention of sporadic CRC and theragnostic biomarkers for assessing efficacy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217885"},"PeriodicalIF":9.1000,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304383525004537","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The cost of cancer care globally is unsustainable and strategies to reduce the mounting burden of cancer are urgently needed. One approach is the use of preventive therapies to reduce cancer risk; dietary-derived compounds with good safety profiles represent a promising source of potential candidates but translating encouraging preclinical data to successful trials presents significant challenges. Development of curcumin, from the spice turmeric, as a preventive therapy for colorectal cancer (CRC) is hindered by poor understanding of its mechanism of action. Using patient derived xenografts and ex-vivo 3D-models exposed to clinically achievable curcumin concentrations, we found that it targets proliferating cancer stem-like cells (CSCs) within premalignant adenoma and early-stage cancer tissues, with broad spectrum activity across all molecular subtypes. Transcriptomics analysis revealed that curcumin pushes CSCs towards differentiation over self-renewal, thereby inhibiting tumour development. Evidence suggests these effects involve direct protein binding of curcumin to NANOG, a master regulator of CRC CSCs, and impairment of its transcriptional activity via direct interference with NANOG-DNA binding. Furthermore, curcumin decreased the proportion of proliferating CSCs, defined by NANOG/Ki67 co-expression in patient derived explants and individuals with tumours containing a small fraction of these cells had greatly improved progression-free survival compared to those in the highest quartile for expression. The use of curcumin to minimise this cellular population may yield significant benefit and its clinical evaluation is warranted. Overall, this study provides crucial mechanistic insight, identifying patient populations likely to benefit from curcumin for prevention of sporadic CRC and theragnostic biomarkers for assessing efficacy.
期刊介绍:
Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research.
Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy.
By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.