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Nature Microbiology Oct 2022Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host...
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 -
Cell Reports Aug 20225-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA...
5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.
Topics: Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Humans; Mitochondria; Neoplasms; Nucleotides; Serine
PubMed: 35977477
DOI: 10.1016/j.celrep.2022.111233 -
Gut Microbes 2023Probiotic roles of (C.B) are involved in regulating disease and cancers, yet the mechanistic basis for these regulatory roles remains largely unknown. Here, we...
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 -
Cell Reports Nov 2022Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis....
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 -
EBioMedicine Apr 2023More than ten randomized clinical trials are being tested to evaluate the efficacy, effectiveness and safety of a fasting-mimicking diet (FMD) combined with different...
BACKGROUND
More than ten randomized clinical trials are being tested to evaluate the efficacy, effectiveness and safety of a fasting-mimicking diet (FMD) combined with different antitumor agents.
METHODS
UMI-mRNA sequencing, Cell-cycle analysis, Label retention, metabolomics, Multilabeling et al. were used to explore mechanisms. A tandem mRFP-GFP-tagged LC3B, Annexin-V-FITC Apoptosis, TUNEL, H&E, Ki-67 and animal model was used to search for synergistic drugs.
FINDINGS
Here we showed that fasting or FMD retards tumor growth more effectively but does not increase 5-fluorouracil/oxaliplatin (5-FU/OXA) sensitivity to apoptosis in vitro and in vivo. Mechanistically, we demonstrated that CRC cells would switch from an active proliferative to a slow-cycling state during fasting. Furthermore, metabolomics shows cell proliferation was decreased to survive nutrient stress in vivo, as evidenced by a low level of adenosine and deoxyadenosine monophosphate. CRC cells would decrease proliferation to achieve increased survival and relapse after chemotherapy. In addition, these fasting-induced quiescent cells were more prone to develop drug-tolerant persister (DTP) tumor cells postulated to be responsible for cancer relapse and metastasis. Then, UMI-mRNA sequencing uncovered the ferroptosis pathway as the pathway most influenced by fasting. Combining fasting with ferroptosis inducer treatment leads to tumor inhibition and eradication of quiescent cells by boosting autophagy.
INTERPRETATION
Our results suggest that ferroptosis could improve the antitumor activity of FMD + chemotherapy and highlight a potential therapeutic opportunity to avoid DTP cells-driven tumor relapse and therapy failure.
FUNDING
A full list of funding bodies can be found in the Acknowledgements section.
Topics: Animals; Ferroptosis; Neoplasm Recurrence, Local; Antineoplastic Agents; Oxaliplatin; Fluorouracil; Apoptosis; Fasting; Cell Line, Tumor; RNA, Messenger; Colorectal Neoplasms
PubMed: 36863257
DOI: 10.1016/j.ebiom.2023.104496 -
Matrix Biology : Journal of the... Jan 2023The mechanical microenvironment regulated by cancer-associated fibroblasts (CAFs) influence tumor progression. Chemotherapeutic interventions including 5-Fluorouracil...
The mechanical microenvironment regulated by cancer-associated fibroblasts (CAFs) influence tumor progression. Chemotherapeutic interventions including 5-Fluorouracil (5-Fu) are commonly used for primary treatment of patients with advanced gastric cancer (GC), and the development of acquired resistance to 5-Fu limits the clinical efficacy of these chemotherapies. However, if and how the interplay between CAFs and the mechanical microenvironment regulates GC response to 5-Fu is poorly understood. In this study, we demonstrate that high-level expression of calponin 1(CNN1) in gastric CAFs predicts poor clinical outcomes of GC patients, especially for those treated with 5-Fu. CNN1 knockdown in CAFs improves the effectiveness of 5-Fu in reducing tumor growth in a mouse GC model and confers increased sensitivity to 5-Fu in a 3D culture system. Furthermore, CNN1 knockdown impairs CAF contraction and reduces matrix stiffness without affecting the expression of matrix proteins. Mechanistically, CNN1 interacts with PDZ and LIM Domain 7 (PDLIM7) and prevents its degradation by the E3 ubiquitin ligase NEDD4-1, which leads to activation of the ROCK1/MLC pathway. The increased matrix stiffness, in turn, contributes to 5-Fu resistance in GC cells by activating YAP. Taken together, our data reveal a critical role of the mechanical microenvironment in 5-Fu resistance, which is modulated by CNN1 CAFs-mediated matrix stiffening, indicating that targeting CAFs may provide a novel option for overcoming drug resistance in GC.
Topics: Animals; Mice; Stomach Neoplasms; Drug Resistance, Neoplasm; Cancer-Associated Fibroblasts; Cell Line, Tumor; Fluorouracil; Tumor Microenvironment; Calponins
PubMed: 36423735
DOI: 10.1016/j.matbio.2022.11.005 -
The British Journal of Ophthalmology Oct 1991
Topics: Child; Cicatrix; Fluorouracil; Glaucoma; Humans; Trabeculectomy
PubMed: 1954203
DOI: 10.1136/bjo.75.10.577 -
Nature Communications Jan 2024How 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...
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 -
Journal of Clinical Oncology : Official... Feb 2015This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast... (Randomized Controlled Trial)
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.
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 -
Expert Reviews in Molecular Medicine Jan 2022Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and... (Review)
Review
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