Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.
Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
Int J Mol Sci. 2024 Jul 8;25(13):7470. doi: 10.3390/ijms25137470.
Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.
结直肠癌（CRC）是一个重大的公共卫生挑战，5-氟尿嘧啶（5-FU）耐药性是有效治疗的主要障碍。尽管取得了进展，但由于药物转运改变、逃避细胞凋亡、细胞周期动力学失调、肿瘤微环境（TME）相互作用以及细胞外囊泡（EV）介导的耐药途径等复杂机制，5-FU 耐药仍然是一个巨大的挑战。传统化疗往往毒性较高，这凸显了需要具有更好疗效和安全性的替代方法。植物化学物质（PCs）和 EVs 为 CRC 的治疗提供了有前途的策略。PCs 来源于天然来源，通常毒性较低，可以靶向参与癌症进展和耐药的多个途径。EVs 可以促进靶向药物递送、调节免疫反应，并与 TME 相互作用，使癌细胞对治疗敏感。然而，PCs 和工程 EVs 在克服 5-FU 耐药性和重塑 CRC 中的免疫抑制 TME 方面的潜力尚未得到充分探索。解决这一差距对于确定具有增强疗效和降低毒性的创新疗法至关重要。本综述探讨了 5-FU 在 CRC 中耐药的多方面机制，并评估了将 PCs 与 5-FU 联合使用以提高治疗效果同时最小化不良反应的协同作用。此外，它还研究了工程 EVs 作为药物递送载体和调节 TME 来克服 5-FU 耐药性的作用。通过综合当前的知识并解决研究空白，本综述增强了结直肠癌中 5-FU 耐药性的学术理解，强调了涉及 PCs 和 EVs 的跨学科方法在彻底改变 CRC 治疗方面的潜力。进一步的研究和临床验证对于将这些发现转化为改善患者预后至关重要。
