A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate

Abstract

5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.

Emerging Nanotheranostics for 5-Fluorouracil in Cancer Therapy: A Systematic Review on Efficacy, Safety, and Diagnostic Capability

“…Despite being an old drug with several known limitations, 5-fluorouracil remains an essential component of numerous chemotherapy regimens owing to its unique and lethal anticancer mechanism of action ( Chalabi-Dchar et al, 2021 ). With the convergence of innovation in nanotheranostics, the true anticancer potential of 5-fluorouracil will be realized and potentially further extended to benefit other anticancer agents.…”

Assessment of Alpha-fetoprotein levels and the effect of 5- Fluorouracil on Cytotoxicity of HepG2 cell line

“…5-Fluorouracil (5-FU) was discovered as antimetabolite chemotherapy in 1957 and was licensed by the FDA in 1962 to treat colorectal cancer (CRC) based on the fact that tumoral tissues metabolized uracil more rapidly than normal tissues [44]. Since its initial licensure, 5-FU has been widely used alone or in combination with other medications to treat a variety of solid malignancies of the digestive tract (colorectal, anal, pancreatic, oesophageal, gastric, and ampullary tumors), as well as cancers of other organs (i.e., breast, cervix, and head and neck cancers) [45]. Today, 5-FU is used to treat several of the most lethal forms of cancer, including pancreatic ductal adenocarcinoma(PDAC), as well as colorectal cancer (CRC), which are both types of cancer in the digestive system [45].…”

“…Since its initial licensure, 5-FU has been widely used alone or in combination with other medications to treat a variety of solid malignancies of the digestive tract (colorectal, anal, pancreatic, oesophageal, gastric, and ampullary tumors), as well as cancers of other organs (i.e., breast, cervix, and head and neck cancers) [45]. Today, 5-FU is used to treat several of the most lethal forms of cancer, including pancreatic ductal adenocarcinoma(PDAC), as well as colorectal cancer (CRC), which are both types of cancer in the digestive system [45]. While treatment regimens (dosage, timing, and delivery) vary according to the tumor's genesis, 5-FU remains a critical medicine for cancer management [46].…”

Nutraceutical-Based Nanoformulations for Breast and Ovarian Cancer Treatment

“…DHA was reported to induce the expression of BCa non-coding microRNA let-7a , which functions as a tumor suppressor and, when it is reduced, is associated with tumorigenesis, poor prognosis and chemoresistance in different cancers, including BCa [ 80 , 81 , 82 ]. Since the chemoterapic drug 5-fluorouracil (5-FU) had been observed to exert the same inducing effect as DHA on let-7a expression [ 83 , 84 ], Li et al [ 85 ] designed a nanosystem with magnetization for the delivery of 5-FU consisting of a porous zirconium-based metal-organic framework (MOF) UIO-66-NH2 bound to DHA. The authors chose this MOF for its feature of low cytotoxicity and high biocompatibility, which makes it an optimal carrier for drug delivery [ 86 ].…”