An old spice with new tricks: Curcumin targets adenoma and colorectal cancer stem-like cells associated with poor survival outcomes

IF 9.1 1区 医学 Q1 ONCOLOGY
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
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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.
有了新花样的老香料:姜黄素靶向与生存率低相关的腺瘤和结直肠癌干细胞样细胞。
全球癌症治疗的费用是不可持续的,迫切需要采取战略来减轻日益沉重的癌症负担。一种方法是使用预防疗法来降低癌症风险;具有良好安全性的膳食衍生化合物是一个有希望的潜在候选来源,但将令人鼓舞的临床前数据转化为成功的试验存在重大挑战。姜黄素,来自香料姜黄,作为结直肠癌(CRC)的预防治疗的发展受到其作用机制了解不足的阻碍。利用患者来源的异种移植物和暴露于临床可达到的姜黄素浓度的离体3d模型,我们发现姜黄素靶向癌前腺瘤和早期癌症组织中的增殖性癌症干细胞(CSCs),在所有分子亚型中具有广谱活性。转录组学分析显示,姜黄素推动CSCs向自我更新的分化,从而抑制肿瘤的发展。有证据表明,这些影响涉及姜黄素与NANOG (CRC CSCs的主要调节因子)的直接蛋白结合,以及通过直接干扰NANOG- dna结合而损害其转录活性。此外,姜黄素降低了增殖CSCs的比例,通过NANOG/Ki67在患者来源的外植体中的共表达来定义,与表达最高四分位数的个体相比,含有少量这些细胞的肿瘤个体的无进展生存期大大提高。使用姜黄素来减少这种细胞数量可能会产生显著的益处,其临床评估是有必要的。总的来说,这项研究提供了关键的机制见解,确定了可能受益于姜黄素预防散发性结直肠癌的患者群体和评估疗效的诊断性生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
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.
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