Capecitabine Research Articles (Page 1)

Breast cancer is one of the most frequently diagnosed cancers worldwide. Although chemotherapy remains a prevalent treatment, it negatively affects patients' quality of life. In this regard, probiotics emerge as possible adjuvants. The aim of this study was to evaluate two lactic acid bacteria (LAB) selected for their immunomodulatory properties, Streptococcus thermophilus CRL807 and Lactobacillus delbrueckii subsp. bulgaricus CRL864, in a breast cancer model undergoing chemotherapy with capecitabine (CAP) or 5-fluorouracile (5-FU). 4T1 breast cancer cells were injected into the upper mammary gland of adult female mice. After tumour reached an appropriate size, mice were separated into groups (N = 10) receiving either individual LAB (100µl of 9 ± 1 x 108 CFU/ml) or yoghurt (2 ± 1 108 CFU/ml ad libitum) with or without chemotherapy. The results showed that administration of LAB or yoghurt resulted in a significant reduction in tumour size and weight (about 50%), modulating the immune response, with increases of IL-10 in mice with smaller tumours, and without afecting chemotherapy. Furthermore, consumption of LAB or yoghurt decreased the negative side-effects associated with these treatments. Yoghurt showed the best results in preventing weight loss, with lower mortality (20 % vs 40 % for 5-FU treatment), maintaining intestinal histology, and modulating plasma cytokines, with increases of IL-10. In conclusion, administration of this probiotic yoghurt was safe in cancer hosts undergoing chemotherapy, reducing some associated negative side effects without intefering with the primary cancer treatment. Furthermore, this yoghurt showed beneficial properties against the tumour, modulating the host's immune response.

Recent data demonstrate that one possibility for increasing Peptide Receptor Radionuclide Therapy (PRRT) results lies in the combination of PRRT with chemotherapy. This study aimed to evaluate response and outcome in [18F]FDG-positive metastatic neuroendocrine tumor (mNET) patients treated with PRRT alone or in combination with temozolomide (TEM) plus/minus capecitabine (CAP). All mNET patients presented with [18F]FDG-positive disease prior to treatment (or retreatment) with PRRT alone or in combination with chemotherapy were retrospectively included in this single-center study. Patients received [177Lu]Lu-DOTATATE with an activity of 7.4 GBq alone or combined with TEM (200mg/kg/5d) plus/minus CAP (1500mg/kg/14d). Contrast-enhancement CT (ceCT), [68Ga]Ga-DOTATOC and [18F]FDG PET/CT studies were performed at baseline, after treatment, and every 6 months thereafter. Overall response rate (ORR) and disease control rate (DCR) were calculated for each group. Survival analysis was performed using the Kaplan-Meier method. Adverse events were collected and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. A total of 24 patients were included in the final analysis. Group 1 received PRRT with [177Lu]Lu-DOTATATE alone (n = 10), group 2 received [177Lu]Lu-DOTATATE plus TEM (n = 7), and group 3 received [177Lu]Lu-DOTATATE plus CAPTEM (n = 7). There were no differences between groups in terms of clinicopathological features before treatment. The pancreas was the primary tumor site in 58%, and 92% of patients had more than three liver metastases. Based on [68Ga]Ga-DOTATOC PET/CT and ceCT, in group 1 the ORR and DCR were 10% and 50%, respectively. [18F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 2, the ORR and DCR were 14% and 43%, respectively. [18F]FDG PET/CT showed 2 responders (1 CR, 1 PR). In group 3, the ORR and DCR were 71%, respectively. [18F]FDG PET/CT showed 5 responders (3 CR, 2 PR). In the latter group, 4/7 patients had not progressed and 5/7 were still alive at the time of analysis after a median follow-up of 31 months. Our results show PRRT combined with CAPTEM as the most promising regimen, achieving higher response rates in [¹⁸F]FDG-positive mNETs compared with PRRT alone or PRRT plus TEM. Further studies are required to confirm its added value in terms of survival outcomes. No increased toxicity seems to be associated with combination therapy compared to PRRT alone.

Exploring the potential of a quick and simultaneous DoE-based stability indicating novel RP-HPLC method for the estimation of capecitabine and curcumin in biodegradable nanoparticles and human plasma.

2100P Tislelizumab (TIS) with or without capecitabine (CAP) continuation in gastric or gastro-oesophageal junction cancer (GC/GEJC): RATIONALE-305 post hoc analysis

Glioblastoma multiforme (GBM), the most aggressive brain cancer, is highly resistant to chemotherapy, which profoundly affects patient survival and prognosis. Temozolomide (TMZ), the sole first-line chemotherapeutic agent for GBM, faces substantial challenges in overcoming this resistance. Despite the belief that TMZ is well-absorbed in the small intestine and can effectively cross the blood-brain barrier due to its small molecular size, emerging evidence suggests that its uptake is not merely through passive diffusion across the lipid bilayer but is regulated by Wnt signaling. However, the precise mechanism governing TMZ uptake remains elusive. GLUT3, which is highly expressed in GBM and primarily functions as a glucose transporter, has emerged as a promising therapeutic target. This study demonstrates that GLUT3 upregulation in GBM cells enhances sensitivity to both TMZ and capecitabine (CAPE). Uptake assays revealed that GLUT3 overexpression (OE) or knockdown (KD) significantly influenced the uptake of these chemotherapeutic agents. We further validated the interaction between GLUT3 and TMZ/CAPE through molecular docking, dynamics simulations, and MST assay. Site-directed mutagenesis identified eight amino acids involved in GLUT3-mediated binding and transport of TMZ and CAPE. A mouse xenograft model confirmed that GLUT3 OE significantly increases TMZ/CAPE uptake and cytotoxicity, particularly under fasting conditions. Our findings establish GLUT3 as a multifunctional transporter for TMZ, CAPE, and glucose, thereby enhancing GBM chemosensitivity. These results challenge the prevailing notion that GLUT3’s role in tumors is solely related to glucose transport. Our work suggests tailoring chemotherapy based on GLUT3 expression level in GBM patients and reevaluating GLUT inhibitors in combination with chemotherapeutic agents.

Capecitabine (CAP) is a chemotherapeutic drug used via oral administration for the management of metastatic cancers of the breast and colon. CAP is a prodrug of 5-fluorouracil, which inhibits DNA synthesis and slows tumor growth. The objective of the current research was to develop colon-targeting CAP-loaded microsponges by using the quasi-emulsion solvent diffusion technique employing Hydroxypropyl Cellulose (HPC) and Ethyl Cellulose (EC) as constituent polymers at different ratios with varying stirring speeds (rpm). In the present study, CAP-loaded microsponges were formulated by using the quasiemulsion solvent diffusion method with HPC and EC as polymers at different ratios with varying stirring speeds. The 32-factorial design was used to perform the statistical optimization of CAPloaded microsponges. The in vivo pharmacokinetic study of the optimized formulation of CAP-loaded microsponges was performed using Albino Wistar Rats. Based on the statistical optimization, the F1 formulation prepared using a 1:1 ratio of HPC and EC with 1000 rpm stirring speed was selected for its effective drug release (31.13 ± 1.73% after 8 hours and 69.57 ± 2.53% after 12 hours) and the highest drug entrapment efficiency (73.09 ± 3.54%). The high Cmax, low tmax, and 1.48-fold improvement in AUC0-∞ indicated that the optimized formulation of CAP-loaded microsponges, compared to an aqueous solution of CAP, revealed a significant (p<0.05) improvement in bioavailability of CAP when administered orally. These findings indicated the potential delivery of CAP by these CAP-loaded microsponges to the colon, enabling sustained delivery and improving the bioavailability of CAP. However, comparative evaluation with existing market formulation and stability studies is essential to validate its therapeutic implications. The developed CAP-loaded microsponges could serve as an effective carrier for the sustained release of CAP, thereby improving the oral bioavailability of CAP for the management of colon cancer.

In this study, a pH-responsive molecularly imprinted polymer (MIP) drug carrier was developed utilizing boric acid-functionalized mesoporous silica nanoparticles (MSNs) as the substrate. The carrier was engineered for controlled drug release, with capecitabine (CAPE) being selected as the template molecule due to its structural characteristics and clinical relevance. In vitro drug release studies demonstrated the pH-responsive release behaviors of the fabricated carrier, highlighting its promising applicability in the controlled release of pharmaceutical compounds containing cis-diols, particularly for site-specific therapy where pH variations serve as physiological triggers.

Background: Cancer has emerged as a critical global health concern due to its widespread prevalence and impact on individuals, families, communities, and healthcare systems worldwide.Objective: We investigated the anticancer effectiveness of capecitabine (CAP) and vorinostat (VOR) when incorporated into self-nanoemulsifying drug delivery systems (SNEDDSs).Material and Methods:In this experimental study, the SNEDDSs were formulated using polyethylene glycol 600 (PEG 600), castor oil and Tween 80. A ternary phase diagram was plotted forthe SNEDDSs components and the single-phase formation region was attained. SNEDDSs were then prepared by dilution of the selected ratios of these components in water.Blank SNEDDSs containing ratios (in weight) of castor oil:Tween 80:PEG 600 of 50:30:20 (S1-SNEDDS) and 25:15:60 (S2-SNEDDS) were selected. S1-SNEDDS was loaded with CAP (S1-SNEDDS-CAP), and S2-SNEDDS was loaded with VOR (S2-SNEDDS-VOR). Results: The developed SNEDDSs formed oil nanodroplets without phase separation. Using dynamic laser light scattering, S1-SNEDDS, S2-SNEDDS, S1-SNEDDS-CAP and S2-SNEDDS-VORhad droplets with average sizes of 171±37, 82±18, 117±26 and 37±8 nm, respectively, accompanied by span values of 0.96, 0.95, 0.97 and 0.96, respectively.CAP and VOR were effectively loaded into the SNEDDSs with high entrapment efficiencies and loading capacities. Considerable improvements in cells viabilityfor CAP and VOR were attained upon loading into SNEDDSs. TUNEL assays of the cells upon treatment by S1-SNEDDS-CAP and S2-SNEDDS-VOR revealed a significant apoptosis in all the cells. Conclusion: The study provides valuable insights into the potential of utilizing SNEDDSs as a novel delivery system for improving the anticancer properties of CAP and VOR.

Abstract Background: T-DXd is approved in over 55 countries for patients with HER2-low (immunohistochemistry [IHC] 1+, IHC 2+ / negative results on in situ hybridization), unresectable/metastatic breast cancer (mBC) who received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 explored the safety, tolerability, and antitumor activity of T-DXd combinations in HER2-low mBC (NCT04556773). Results reported here are from the final data cutoff (DCO) of the dose-expansion phase (Part 2) of DESTINY-Breast08, for T-DXd + capecitabine (CAPE) and T-DXd + capivasertib (CAPI). Methods: Eligible patients had locally confirmed HER2-low mBC with measurable disease per RECIST 1.1. In the T-DXd + CAPE arm, patients with hormone receptor–negative (HR−) or HR-positive (HR+) disease were eligible. In the T-DXd + CAPI arm, patients with HR− disease were eligible. Across both arms, patients with HR− mBC were allowed ≤1 prior line of chemotherapy. In the T-DXd + CAPE arm, patients with HR+ mBC were allowed ≤1 prior line of endocrine therapy ± a targeted therapy for mBC, with no prior chemotherapy in the metastatic setting. Patients received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) + CAPE 750 mg/m2 orally (PO) twice daily (BID) on Days 1–14 Q3W, or 5.4 mg/kg T-DXd IV Q3W + CAPI 400 mg PO BID every week on Days 1–4 within a 21-day treatment cycle. Primary objectives were safety and tolerability; key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS) by investigator per RECIST 1.1, overall survival (OS), and duration of response (DOR). Results: As of August 16, 2023, 20 patients in the T-DXd + CAPE arm and 40 patients in the T-DXd + CAPI arm had received study treatment. Median age was 57.5 and 56.0 years, respectively. In the T-DXd + CAPE arm, 30.0% (n=6/20) of patients had HR− mBC, and 70.0% (n=14/20) of patients had HR+ mBC. In the T-DXd + CAPI arm, 32.5% (n=13/40) of patients had centrally confirmed AKT/PTEN/PIK3CA alterations detected by ctDNA assays. In patients with HR− disease, 83.3% (n=5/6) and 45.0% (n=18/40) received first-line chemotherapy for mBC in the T-DXd + CAPE and T-DXd + CAPI arms, respectively. In patients with HR+ disease in the T-DXd + CAPE arm, 64.3% (n=9/14) had received first-line hormonal therapy ± a targeted therapy for mBC. Median actual treatment duration was 11.1 months for T-DXd and 7.0 months for CAPE in the T-DXd + CAPE arm, and 6.2 months for T-DXd and 5.5 months for CAPI in the T-DXd + CAPI arm. Grade ≥3 adverse events (AEs) occurred in 55.0% (n=11/20) and 67.5% (n=27/40) of patients treated with T-DXd + CAPE and T-DXd + CAPI, respectively. Serious AEs were reported in two patients (10.0%) in the T-DXd + CAPE arm, and 13 patients (32.5%) in the T-DXd + CAPI arm. Three (15.0%) adjudicated drug-related interstitial lung disease / pneumonitis events were reported in the T-DXd + CAPE arm (Grade 2, n=2; Grade 5, n=1) and eight (20.0%) in the T-DXd + CAPI arm (Grade 1, n=1; Grade 2, n=7). Confirmed ORR was 60.0% for both T-DXd + CAPE and T-DXd + CAPI. At final DCO, median DOR was not reached for T-DXd + CAPE but was 7.1 months for T-DXd + CAPI. Median PFS was 13.4 months and 9.0 months for T-DXd + CAPE and T-DXd + CAPI, respectively. Median follow-up duration was 15.2 months and 8.6 months for T-DXd + CAPE and T-DXd + CAPI, respectively. OS was not mature at final DCO for either arm; the survival rate at 12 months was 78.0% (95% confidence interval [CI] 51.5, 91.1) for T-DXd + CAPE and 92.0% (95% CI 77.2, 97.4) for T-DXd + CAPI. Conclusion: Safety profiles for T-DXd + CAPE and T-DXd + CAPI were generally consistent with the known safety profile of each agent, and both combinations demonstrated antitumor activity; further research is warranted. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey K Anders, Hans Wildiers, Yeon Hee Park, Shin-Cheh Chen, Caron Lloyd, Karen Cui, Cuihong Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with capecitabine or capivasertib in patients with HER2-low metastatic breast cancer: a Phase 1b, multicenter, open-label study (DESTINY-Breast08) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-17.

Dose-limiting toxicities pose a major barrier to cancer treatment. While preclinical studies show that the gut microbiota influences and is influenced by anticancer drugs, data from patients paired with careful side effect monitoring remains limited. Here, we investigate capecitabine (CAP)-microbiome interactions through longitudinal metagenomic sequencing of stool from 56 advanced colorectal cancer patients. CAP significantly altered the gut microbiome, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, and media supplementation revealed that menaquinol biosynthesis protects Escherichia coli from drug toxicity. Stool menaquinol gene and metabolite levels were associated with decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted toxicities in an independent cohort. Taken together, these results suggest treatment-associated increases in microbial vitamin biosynthesis serve a chemoprotective role for bacterial and host cells. Further, our findings provide a foundation for in-depth mechanistic dissection, human intervention studies, and extension to other cancer treatments.IMPORTANCESide effects are common during the treatment of cancer. The trillions of microbes found within the human gut are sensitive to anticancer drugs, but the effects of treatment-induced shifts in gut microbes for side effects remain poorly understood. We profiled gut microbes in colorectal cancer patients treated with capecitabine and carefully monitored side effects. We observed a marked expansion in genes for producing vitamin K2 (menaquinone). Vitamin K2 rescued gut bacterial growth and was associated with decreased side effects in patients. We then used information about gut microbes to develop a predictive model of drug toxicity that was validated in an independent cohort. These results suggest that treatment-associated increases in bacterial vitamin production protect both bacteria and host cells from drug toxicity, providing new opportunities for intervention and motivating the need to better understand how dietary intake and bacterial production of micronutrients like vitamin K2 influence cancer treatment outcomes.

This work aimed to improve the peroral bioavailability of capecitabine (CPB) by developing and assessing solid lipid nanoparticles (SLNs). SLNs were made using the modified nanoprecipitation method. Particle size, zeta potential, entrapment efficiency, drug loading, in-vitro drug release, TEM, in-vivo pharmacokinetic study, stability study, histopathological evaluation and cytotoxicity study were assessed. The TEM revealed that the SLNs were transparent, with a mean particle size ranging from 13.06 ± 0.09 to 86.10 ± 0.15 nm. The F-3 formulation demonstrated the highest drug entrapment efficiency at 45.49 ± 0.28. The zeta potential and polydispersity index of all SLNs ranged from −15.53 ± 0.17 to 17.55 ± 0.18 mV and from 0.1356 ± 0.11 to 0.2678 ± 0.13, respectively. The drug entrapment efficiency and drug loading of all SLNs ranged from 18.45 ± 0.36 to 45.49 ± 0.28 and from 21.75 ± 0.64 to 59.49 ± 0.38, respectively. The CPB-SLNs showed sustained drug release with prolonged plasma retention, delayed Tmax, and extended half-life compared to raw CPB. In vivo pharmacokinetic studies suggest that developed SLNs may enhance therapeutic efficacy by maintaining drug concentrations in plasma for longer periods. Toxicity was observed at 200 mg/kg/day, indicated by changes in clinical biochemistry, organ weights, and histopathology, particularly affecting the liver and kidneys. Therefore, it can be said that these developed SLNs may be among the best preparations for the delivery of anti-cancer drugs for improved therapeutic efficacy.

Multi-Organ-on-Chip approach to study the impact of inter-organ communication on the efficacy and side effects of cancer therapy.

Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP). Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses. The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells. These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

Anti-angiogenesis offers an important treatment strategy for metastatic breast cancer (MBC). Metronomic chemotherapy (MCT) provides antiangiogenic effects without increased toxicities, making it good partner for antiangiogenic therapy. We conducted the present retrospective study to evaluate the efficacy and safety of anlotinib plus MCT for HER2 negative MBC. Patients with HER2 negative MBC who received metronomic chemotherapy (Vinorelbine (NVB), Capecitabine (CAPE), Etoposide (VP-16)) with anlotinib were retrospectively analyzed from Jan 2019 to Dec 2021. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. 48 patients with HER2 negative MBC were enrolled. 19 (39.6%) patients received NVB, 17 (35.4%) patients received CAPE and 12 (25.0%) patients received VP-16. The overall ORR and DCR were 8.3% (4/48) and 87.5% (42/48) respectively. The median PFS was 5.6 months (95% CI 4.3-7.0 months), and the median OS was 25.2 months (95% CI 20.2-30.1 months). The patients with age ≥ 50 (5.3 vs. 7.7 months, P = 0.014, HR = 0.407) and pathologic grade 1 or 2 (6.2 vs. 3.2 months, P = 0.023, HR = 2.471) had significantly longer PFS. The patients with hormone receptor (HR) positive (5.3 vs. 7.7 months, P = 0.004, HR = 0.206) and pathologic grade 1 or 2 (6.2 vs. 3.2 months, P = 0.020, HR = 3.882) had significantly longer OS. The incidence of all grades adverse events (AEs) was 56.3% (27/48) and grade 3–4 AEs was 12.5% (6/48). Within the context of real-world clinical practice, anlotinib in combination with metronomic chemotherapy provides a well-tolerated and effective treatment option for HER2-negative MBC, which warrants further investigation in the future.

Hyaluronic acid-coated capecitabine-loaded nanomicelles (HA-CAP-M) are synthesized to overcome the challenges associated with capecitabine (CAP) conventional delivery such as low permeability and systemic toxicity. Nanomicelles containing saponin, glycerol, and vitamin-E TPGS formulation of capecitabine were further encapsulated with hyaluronic acid (HA) for CD44 receptor-mediated targeting. Optimization of the formulation was carried out using a Box-Behnken design resulting in 17.8 nm particle size, 89.3% entrapment efficiency and a biphasic drug release profile. Characterization studies validated stability, spherical structure, and desirable encapsulation characteristics of the nanomicelles. Lowered critical micelle concentration (CMC) and acceptable drug release kinetics revealed improved thermodynamic stability and controlled drug release, as predicted by the Hixson-Crowell model. HA-CAP-M showed much higher permeability and cytotoxicity than the free CAP, with an IC50 of 2.964 μg mL-1 in in vitro experiments. AO/PI staining also demonstrated dose-dependent apoptosis in MCF-7 breast cancer cells and validated the highly effective active targeting of HA. In addition, the formulation demonstrated good stability during storage and dilution conditions, confirming its stability as a drug delivery platform. In conclusion, HA-functionalized nanomicelles provide a biocompatible and efficient system for the targeted breast cancer therapy, enhancing the therapeutic efficacy of capecitabine.

The flavonoid silymarin (SMN) has shown promise due to its antioxidant, anti-inflammatory, and anticancer properties. SMN has been widely used in preclinical and clinical studies to treat various types of cancer, alone and with chemotherapy agents. Recent research suggests that SMN may increase conventional chemotherapy efficacy and reduce adverse effects. Herein, we investigated the therapeutic efficacy of SMN and its combination with capecitabine (CAP) and irinotecan (IRI) in a mouse model of colon cancer. Following 1,2 dimethylhydrazine-induced colon cancer, a modified diet supplemented with SMN (2500 ppm) and mono- and combined therapy of CAP and IRI was used. Serum samples were analyzed for lipid profile, liver function, and inflammatory cytokines. Oxidative stress and inflammation markers, including malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured in colonic, hepatic, and circulatory samples. Colonic BAX and Bcl-2 levels were examined via western blotting and histopathological analysis of colon sections was conducted. SMN alone and combined with chemotherapeutic agents significantly mitigated the elevated inflammatory cytokines liver function enzyme levels, and hyperlipidemia. Furthermore, SMN supplementation with chemotherapy agents enhanced antioxidant activity and reduced lipid peroxidation and inflammatory markers. Significant upregulation of BAX and downregulation of Bcl-2 were observed. In addition, treatment regimens ameliorated carcinogen-induced polyp multiplicity, adenoma formation, dysplastic changes, and lymphocytic aggregation. Our results demonstrated that the potential anticancer properties of SMN could enhance chemotherapy efficacy and reduce carcinogen- and chemotherapy-induced hepatotoxicity.

Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma

Ferrate(Ⅵ) oxidative degradation of capecitabine in aquatic matrices: Degradation performance, mechanisms, and toxicity assessment

Purpose.Unpredictable chemotherapy side effects are a major barrier to successful treatment. Cell culture and mouse experiments indicate that the gut microbiota is influenced by and influences anti-cancer drugs. However, metagenomic data from patients paired to careful side effect monitoring remains limited. Herein, we focus on the oral fluoropyrimidine capecitabine (CAP). We investigate CAP-microbiome interactions through metagenomic sequencing of longitudinal stool sampling from a cohort of advanced colorectal cancer (CRC) patients.Methods.We established a prospective cohort study including 56 patients with advanced CRC treated with CAP monotherapy across 4 centers in the Netherlands. Stool samples and clinical questionnaires were collected at baseline, during cycle 3, and post-treatment. Metagenomic sequencing to assess microbial community structure and gene abundance was paired with transposon mutagenesis, targeted gene deletion, and media supplementation experiments. An independent US cohort was used for model validation.Results.CAP treatment significantly altered gut microbial composition and pathway abundance, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, and media supplementation confirmed that menaquinol biosynthesis protects Escherichia coli from drug toxicity. Microbial menaquinol biosynthesis genes were associated with decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted hand-foot syndrome and dose reductions in an independent cohort.Conclusion.These results suggest treatment-associated increases in microbial vitamin biosynthesis serve a chemoprotective role for bacterial and host cells, with implications for toxicities outside the gastrointestinal tract. We provide a proof-of-concept for the use of microbiome profiling and machine learning to predict drug toxicities across independent cohorts. These observations provide a foundation for future human intervention studies, more in-depth mechanistic dissection in preclinical models, and extension to other cancer treatments.

Abstract Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.