Innovative Strategies to Combat 5-Fluorouracil Resistance in Colorectal Cancer: The Role of Phytochemicals and Extracellular Vesicles

Abstract

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.

Keywords: 5-fluorouracil resistance; colorectal cancer; drug transport; extracellular vesicles; phytochemicals.

Figure 1

5-FU mechanism of action. 5-FU enters CRC cells via passive diffusion and active transport using transporters like equilibrative nucleoside transporter 1 (ENT1). Once inside, it is converted to active metabolites. 5-FU’s metabolites impact RNA and DNA functions, contributing to cell death. One such metabolite, 5-fluorodeoxyuridine monophosphate (FdUMP), inhibits thymidylate synthase (TS), disrupting DNA synthesis by blocking the formation of thymidine monophosphate (dTMP). Other 5-FU metabolites, such as 5-fluorouridine triphosphate (FUTP) and 5-fluoro-2’-deoxyuridine triphosphate (FdUTP), are incorporated into RNA and DNA, respectively, further disrupting their functions and contributing to cell death. The figure was created with BioRender.com.

Figure 2

Mechanisms of 5-FU resistance in CRC. 5-FU resistance in CRC involves multiple complex mechanisms. Primary mechanisms involve improved DNA repair pathways like mismatch repair (MMR) and base excision repair (BER), which assist in fixing DNA damage caused by 5-FU, ultimately decreasing its toxic impacts. Epithelial–mesenchymal transition (EMT) helps cancer cells gain the ability to migrate and invade, a key factor in developing resistance. Cancer stem cells (CSCs) have the ability to self-renew and differentiate, making them naturally resistant to chemotherapy drugs like 5-FU. MiRNAs that are not functioning properly alter the expression of genes involved in drug sensitivity and resistance pathways. DNA methylation and histone modifications can silence tumor suppressor genes and activate genes associated with resistance. Moreover, important signaling pathways such as Wnt/β-catenin, NF-κB, JAK/STAT, and Akt are frequently activated in CRCs that are resistant to 5-FU. Stimulation of these pathways enhances cell growth, viability, and the ability to resist cell death, thus aiding in chemoresistance. Moreover, the upregulation of ATP-binding cassette (ABC) transporters enables a higher efflux of 5-FU from cancer cells, leading to decreased intracellular levels and effectiveness of the treatment. Akt, also referred to as protein kinase B (PKB), has a key role in colorectal cancer (CRC) resistance to 5-FU chemotherapy. Activation of Akt prevents cell death by blocking apoptosis, a vital response triggered by chemotherapy agents such as 5-FU. This hindrance allows cancer cells to escape the toxic effects of 5-FU, thus playing a major role in treatment resistance. Problems in Akt signaling in CRC can happen in different ways, like genetic mutations, amplifications, or changes in growth factors and receptor tyrosine kinases that control it. Moreover, the process of epithelial–mesenchymal transition (EMT) plays a pivotal role in promoting metastasis and resistance to chemotherapy in CRC. EMT involves the transformation of epithelial cells into mesenchymal-like cells, enhancing cancer cell migration, invasion, and resistance to apoptosis-inducing therapies like 5-FU. Understanding these mechanisms is crucial for developing new strategies to overcome 5-FU resistance in CRC. The figure was created with Microsoft PowerPoint, version 2406, accessed on 1 July 2024.

Figure 3

Potential action of PCs that can be used in combination with 5-FU. Combining 5-FU with PCs like curcumin (CUR), resveratrol (RES), epigallocatechin gallate (EGCG), genistein (GEN), geraniol (GER), and thymoquinone (TQ) enhances its efficacy in treating CRC by targeting various resistance mechanisms. Curcumin induces apoptosis, inhibits COX-2, and suppresses cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while resveratrol triggers apoptosis, inhibits cell cycle arrest, and suppresses the NF-kB pathway. EGCG enhances cytotoxicity and targets CSCs, genistein promotes apoptosis and inhibits COX-2 production, geraniol increases 5-FU uptake and reduces TS levels, and TQ targets CSCs and inhibits key signaling pathways like Wnt/β-catenin and PI3K/Akt. These combinations collectively improve 5-FU’s cytotoxic effects, making it more effective against chemoresistant CRC cells. The figure was created with Microsoft PowerPoint.

Figure 4

The combination of 5-FU and EVs. Combining 5-FU with EVs offers a promising approach to cancer treatment. By encapsulating 5-FU into EVs, their stability, solubility, and targeted delivery to cancer cells can be enhanced. Engineered EVs with specific surface markers enable precise cancer cell targeting, minimizing off-target effects, and improving therapeutic efficacy. Additionally, EV-mediated delivery of immunomodulatory agents enhances antitumor immunity and targets cancer stem cells. This innovative approach holds significant promise for improving cancer treatment outcomes by leveraging the unique capabilities of EVs. The figure was created with BioRender.com.

Figure 5

CRC treatment often faces the challenge of 5-FU drug resistance despite existing treatments such as chemotherapy, radiation therapy, surgery, targeted therapy. CSCs, complexity of TME, EMT, autophagy, and epigenetic alterations are the causes of this resistance. Phytochemicals (PCs) can work together with 5-FU to improve treatment effectiveness, reduce side effects, and reshape the tumor environment to make treatment more successful. Additionally, the potential of using engineered EVs to deliver drugs, target cancer cells, and serve as biomarkers is discussed. While challenges remain, this area of research is promising for future CRC treatments. The figure was created with BioRender.com.