Curcumin reverses irinotecan-acquired resistance in DLD1 colorectal cancer cells: Insights from whole transcriptomic data.

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-10-03 DOI:10.1016/j.bcp.2025.117386

Laura Gavrilas, Oana Sava, Loredana Balacescu, Stefan Miron, Doina Miere, Ovidiu Balacescu, Cruceriu Daniel

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Abstract

Acquired resistance to chemotherapy, including irinotecan, remains a major challenge in treating metastatic colorectal cancer (CRC). Natural compounds such as curcumin have demonstrated potential in resensitizing chemoresistant cancer cells to existing therapies. This study investigates curcumin's ability to reverse irinotecan resistance in CRC cells and the underlying molecular mechanisms. An irinotecan-resistant CRC cell line (DLD1_IRI-R) was established by gradually increasing irinotecan exposure. The DLD1 cell line was selected for its intermediate sensitivity to irinotecan among CRC cell lines. Cell sensitivity to irinotecan and curcumin was assessed using the MTT assay, with drug interactions evaluated via the Chou-Talalay method. Apoptosis and cell cycle progression were analyzed by flow cytometry, proliferation by clonogenic assays, and migration in 3D microfluidic systems. Whole-genome transcription profiling was conducted using microarrays, with functional analysis performed in Ingenuity Pathway Analysis. DLD1_IRI-R cells exhibited a 7.17-fold increase in irinotecan resistance, accompanied by reduced proliferation and migration. Resistance acquisition led to dysregulation of genes involved in irinotecan metabolism (CYPs, UGTs, AKRs), efflux transport (ABCs), and ER stress adaptation. The gene coding for the drug target, TOP1, was also inhibited. Curcumin, combined with irinotecan at IC₁₀, reduced irinotecan's IC₅₀ by 3.74-fold, exhibiting strong synergy. Curcumin significantly modulated 3,901 genes (FC > |±2|), inducing apoptosis, disrupting ER stress adaptation, reducing proliferation, and inhibiting migration. It also upregulated TOP1 while suppressing key resistance-associated genes, including 18 CYPs, 4 UGTs, 4 AKRs, and 20 ABCs. These findings suggest that low-dose curcumin effectively reverses irinotecan resistance in CRC cells, enhancing chemotherapy sensitivity and inhibiting metastasis-associated traits.

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姜黄素逆转DLD1结直肠癌细胞伊立替康获得性耐药：来自全转录组学数据的见解

获得性化疗耐药，包括伊立替康，仍然是治疗转移性结直肠癌（CRC）的主要挑战。姜黄素等天然化合物已被证明具有使化疗耐药癌细胞对现有疗法重新敏感的潜力。本研究探讨了姜黄素逆转结直肠癌细胞伊立替康耐药的能力及其潜在的分子机制。通过逐渐增加伊立替康暴露量，建立了耐伊立替康CRC细胞系（DLD1_IRI-R）。选择DLD1细胞系是因为它在结直肠癌细胞系中对伊立替康具有中等敏感性。使用MTT法评估细胞对伊立替康和姜黄素的敏感性，通过Chou-Talalay法评估药物相互作用。通过流式细胞术分析细胞凋亡和细胞周期进程，通过克隆实验分析细胞增殖，并在三维微流体系统中进行迁移。使用微阵列进行全基因组转录分析，并在Ingenuity Pathway analysis中进行功能分析。DLD1_IRI-R细胞对伊立替康的耐药性增加了7.17倍，同时增殖和迁移减少。抗性获得导致参与伊立替康代谢（CYPs、UGTs、AKRs）、外排转运（abc）和内质网应激适应的基因失调。编码药物靶点的基因TOP1也被抑制。姜黄素与伊立替康在IC10时联合使用，可使伊立替康的IC50降低3.74倍，表现出较强的协同作用。姜黄素显著调节3,901个基因（FC > |±2|），诱导细胞凋亡，破坏内质网应激适应，降低细胞增殖，抑制迁移。它还上调了TOP1，同时抑制了关键的抗性相关基因，包括18个CYPs、4个ugt、4个akr和20个abc。这些发现表明，低剂量姜黄素可有效逆转结直肠癌细胞对伊立替康的耐药性，增强化疗敏感性并抑制转移相关特征。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.