Authors: Hyemin Lee, Amber Horbath, Lavanya Kondiparthi...

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

Topics: Humans; Lipid Droplets; Ferroptosis; Fatty Acids, Unsaturated; Lipid Peroxidation; Triglycerides; Cell Cycle Checkpoints; Neoplasms; Diacylglycerol O-Acyltransferase; Fluorouracil

PubMed: 38167301
DOI: 10.1038/s41467-023-44412-7

Authors: Peter Spanogiannopoulos, Than S Kyaw, Ben G H Guthrie...

Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. coli, exhibited high catalytic efficiency for the reductive reaction, decreased the bioavailability and efficacy of oral fluoropyrimidine treatment in mice and was prevalent in the gut microbiomes of colorectal cancer patients. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.

Topics: Animals; Antineoplastic Agents; Bacteria; Escherichia coli; Fluorouracil; Humans; Mammals; Metabolic Networks and Pathways; Mice

PubMed: 36138165
DOI: 10.1038/s41564-022-01226-5

Authors: Hui Xu, Haidan Luo, Jiayu Zhang...

Probiotic roles of (C.B) are involved in regulating disease and cancers, yet the mechanistic basis for these regulatory roles remains largely unknown. Here, we demonstrate that C.B reprograms the proliferation, migration, stemness, and tumor growth in CRC by regulating pivotal signal molecules including MYC. Destabilization of MYC by C.B supplementation suppresses cancer cell proliferation/metastasis, sensitizes 5-FU treatment, and boosts responsiveness of anti-PD1 therapy. MYC is a transcriptional regulator of Thymidylate synthase (TYMS), a key target of the 5-FU. Also MYC is known to impact on PD-1 expression. Mechanistically, C.B treatment of CRC cells results in MYC degradation by enhancing proteasome-mediated ubiquitination, thereby mitigating MYC-mediated 5-FU resistance and boosting anti-PD1 immunotherapeutic efficacy. Together, our findings uncover previously unappreciated links between C.B and CRC cell signaling, providing insight into the tumorigenesis modulating mechanisms of C.B in boosting chemo/immune therapies.

Topics: Humans; Colorectal Neoplasms; Cell Line, Tumor; Clostridium butyricum; Gastrointestinal Microbiome; Cell Proliferation; Fluorouracil

PubMed: 36941257
DOI: 10.1080/19490976.2023.2186114

Authors: Kaitlyn D LaCourse, Martha Zepeda-Rivera, Andrew G Kempchinsky...

Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis. Following a small-molecule inhibitor screen of 1,846 bioactive compounds against a Fn CRC isolate, we find that 15% of inhibitors are antineoplastic agents including fluoropyrimidines. Validation of these findings reveals that 5-fluorouracil (5-FU), a first-line CRC chemotherapeutic, is a potent inhibitor of Fn CRC isolates. We also identify members of the intratumoral microbiota, including Escherichia coli, that are resistant to 5-FU. Further, CRC E. coli isolates can modify 5-FU and relieve 5-FU toxicity toward otherwise-sensitive Fn and human CRC epithelial cells. Lastly, we demonstrate that ex vivo patient CRC tumor microbiota undergo community disruption after 5-FU exposure and have the potential to deplete 5-FU levels, reducing local drug efficacy. Together, these observations argue for further investigation into the role of the CRC intratumoral microbiota in patient response to chemotherapy.

Topics: Humans; Fusobacterium nucleatum; Escherichia coli; Fluorouracil; Microbiota; Colorectal Neoplasms

PubMed: 36384132
DOI: 10.1016/j.celrep.2022.111625

Authors: Jingwen Yuan, Shahid Ullah Khan, Junfeng Yan...

BACKGROUND

5-Fluorouracil (5-Fu) is one of the most commonly used chemotherapy drugs for gastric cancer (GC). But the increase of drug resistance makes the prognosis of patients worse. Studies have shown that Baicalin can not only inhibit various cancers but also increase the sensitivity of cancers to chemotherapy. However, how Baicalin works in chemotherapeutic resistance of GC are unclear.

METHODS

CCK8 (Cell Counting Kit 8) was used to detect the IC50 (half maximal inhibitory concentration) of Baicalin and 5-Fu. Proliferation, migration, and invasion of GC were tested through colony formation assay and transwell assay. Fluorescent probes detected intracellular reactive oxygen species (ROS). RNA-seq (RNA sequencing) detected differentially expressed genes and pathways, and qPCR (Quantitative Real-time PCR) tested the expression of ferroptosis-related genes.

RESULTS

The combination of Baicalin and 5-Fu inhibited GC progression and increased intracellular ROS levels. Both the inhibition of malignant phenotype of gastric cancer cells and the generation of intracellular ROS caused by Baicalin could be saved by the inhibitor of ferroptosis-Ferrostatin-1 (Fer-1). Heat map of enriched differentially expressed genes identified by RNA-seq included four ferroptosis-related genes, and subsequent GO (Gene Ontology) analysis suggested an association between the ferroptosis pathway and Baicalin treatment. The changes in expression of ferroptosis-related genes were validated by qPCR, and the result confirmed that the combination of Baicalin and 5-Fu promoted ferroptosis in GC.

CONCLUSIONS

Baicalin inhibits GC and enhances 5-Fu by promoting ROS-related ferroptosis in GC.

Topics: Humans; Fluorouracil; Stomach Neoplasms; Reactive Oxygen Species; Ferroptosis; Cell Line, Tumor

PubMed: 37295251
DOI: 10.1016/j.biopha.2023.114986

Randomized Controlled Trial

Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.

Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves...

PURPOSE

This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC).

PATIENTS AND METHODS

Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS).

RESULTS

Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2.

CONCLUSION

In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Deoxycytidine; Female; Fluorouracil; Furans; Humans; Ketones; Middle Aged; Taxoids; Young Adult

PubMed: 25605862
DOI: 10.1200/JCO.2013.52.4892

Authors: P T Khaw, I Grierson, R A Hitchings...

Topics: Child; Cicatrix; Fluorouracil; Glaucoma; Humans; Trabeculectomy

PubMed: 1954203
DOI: 10.1136/bjo.75.10.577

Review

Authors: Gerile Naren, Jiaojiao Guo, Qiujuan Bai...

Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.

Topics: Antineoplastic Agents; Female; Fluorouracil; Humans; Male; Neoplasms; Reproduction

PubMed: 35098910
DOI: 10.1017/erm.2022.3

Authors: Yixin Li, Qi Sun, Lingjia Hao...

INTRODUCTION

Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time.

METHODS

Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment.

RESULTS

Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model.

DISCUSSION

5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.

Topics: Fluorouracil; Rabbits; Animals; Liposomes; Humans; Cicatrix, Hypertrophic; Fibroblasts; Keloid; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Collagen; Cell Movement; Administration, Cutaneous

PubMed: 39050869
DOI: 10.2147/IJN.S466221

Authors: Mengying Hong, Yushen Du, Dongdong Chen...

Martynoside (MAR), a bioactive component in several well-known tonic traditional Chinese herbs, exhibits pro-hematopoietic activity during 5-fluorouracil (5-FU) treatment. However, the molecular target and the mechanism of MAR are poorly understood. Here, by adopting the mRNA display with a library of even-distribution (md-LED) method, we systematically examined MAR-protein interactions in vitro and identified the ribosomal protein L27a (RPL27A) as a key cellular target of MAR. Structural and mutational analysis confirmed the specific interaction between MAR and the exon 4,5-encoded region of RPL27A. MAR attenuated 5-FU-induced cytotoxicity in bone marrow nucleated cells, increased RPL27A protein stability, and reduced the ubiquitination of RPL27A at lys92 (K92) and lys94 (K94). Disruption of MAR binding at key residues of RPL27A completely abolished the MAR-induced stabilization. Furthermore, by integrating label-free quantitative ubiquitination proteomics, transcriptomics, and ribosome function assays, we revealed that MAR restored RPL27A protein levels and thus rescued ribosome biogenesis impaired by 5-FU. Specifically, MAR increased mature ribosomal RNA (rRNA) abundance, prevented ribosomal protein degradation, facilitated ribosome assembly, and maintained nucleolar integrity. Collectively, our findings characterize the target of a component of Chinese medicine, reveal the importance of ribosome biogenesis in hematopoiesis, and open up a new direction for improving hematopoiesis by targeting RPL27A.

Topics: Fluorouracil; Biological Assay; Bone Marrow Cells; Caffeine

PubMed: 37481436
DOI: 10.1016/j.scib.2023.07.018