5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition

Sethy, Chinmayee; Kundu, Chanakya Nath

doi:10.1016/j.biopha.2021.111285

Cited by 250 publications

(184 citation statements)

References 107 publications

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“…Altogether, these studies reveal that 5-FU dysregulates a variety of DNA-based mechanisms, namely the inhibition of TS activity, mis-incorporation into DNA and defective DNA repair. While these types of dysregulation undoubtedly contribute to the cytotoxic effects of 5-FU ( 49 ), a growing body of evidence suggests that 5-FU cytotoxicity is also a substantial consequence of defects in RNA metabolism.…”

Section: Background and Novelties Of 5-fu Integration Into Rna A Revisited Interplaymentioning

confidence: 99%

“…These translationally up-regulated genes are implicated in transcription regulation and have roles in the translational machinery including translation initiation and elongation factors, tRNA maturation factors and ribosomal proteins (the genes are indicated in ( 94 ) Supplementary Table S3). Among the mRNAs whose translation is up-regulated in response to 5-FU, some are involved in pathways controlling cell proliferation and tumorigenesis such as Wnt and integrin signalling pathways also known as pathways involved in 5-FU resistance ( 49 , 95 ) (Table 2 ). Again, this suggests that translational control could be part of the cell response mechanisms that finally lead to reshape gene expression regulation favouring emergence of resistant cells.…”

Section: -Fu Integration In Rrna Generates the Fluorinated Ribosome (F-ribosome)mentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Background and Novelties Of 5-fu Integration Into Rna A Revisited Interplaymentioning

confidence: 99%

Section: -Fu Integration In Rrna Generates the Fluorinated Ribosome (F-ribosome)mentioning

confidence: 99%

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

et al. 2021

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“…The administration of systemic chemotherapies is the mainstay treatment to achieve an improvement in quality of life and survival in about 30% of cancer patients that present advanced and unresectable disease. The drug 5-fluorouracil (5-FU) has been the first chemotherapeutic choice for the treatment of CRC in the last few years [3,6,7]. The overall response rate to 5-FU in advanced CRC is limited to 10-15%.…”

Section: Introductionmentioning

confidence: 99%

“…Although irinotecan and oxaliplatin are usually used in combination with 5-FU to improve survival, toxicity still increases. Indeed, despite initially impressive clinical responses, it is not uncommon to observe phenomena of intrinsic or acquired drug resistance and/or multidrug-resistance (MDR) events that lead to a loss of chemotherapy efficacy, CRC recurrence, and high mortality rate [3,4,6].…”

Section: Introductionmentioning

confidence: 99%

S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

Mosca

Pagano

Borzacchiello

et al. 2021

IJMS

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Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.

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“…[4] Despite 5-FU is a class of broad-spectrum antitumor drugs, drug resistance has greatly affected the clinical use of 5-FU. [5] Therefore, improving drug resistance and drug response rate is a potential research direction.…”

Section: Introductionmentioning

confidence: 99%

A Porphyrin‐Based 5‐Fluorouracil and Its Metal Complexes: Synthesis, Optical Properties, and Antitumor Activity

et al. 2021

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The novel porphyrin-based 5-fluorouracil and its metal complexes were synthesized. Through the combination of porphyrin and anticancer drug 5-fluorouracil (5-FU), it provides ideas for how to maximize the antitumor activity of drugs. The new porphyrin and its metal complexes take advantage of the enrichment of porphyrins in tumor cells, which makes them have higher cytotoxicity to tumor cells than normal cells, thus reducing the toxic and side effects. Excellent photophysical properties were illustrated by UV-vis absorption and emission spectra with enhanced absorbance between 650 and 750 nm and fluorescence emission within 600-800 nm. Besides, manganese porphyrin and non-central metalloporphyrin were evaluated in vitro by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay against MCF-7, HepG2, and HeLa. In addition, compared with free 5-fluorouracil, the novel manganese porphyrin shows higher antitumor activity. Therefore, the novel manganese porphyrin-based 5-fluorouracil is a promising drug for cancer treatment due to its effective antitumor activity, and near-infrared absorption.

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5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition

Cited by 250 publications

References 107 publications

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

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

S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

A Porphyrin‐Based 5‐Fluorouracil and Its Metal Complexes: Synthesis, Optical Properties, and Antitumor Activity

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