EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 6.7
Ya-Kun Zhang,Jian-Bo Tong,Hong-Yan Zhang,Zhi-Peng Qin,Cheng-Jian Tan
A bioactivity repurposing strategy expanded the potential pharmacological applications of sophoridine derivatives. • Sophoridine derivatives modulated the Topo I–DNA catalytic system and exhibited preliminary antitumor activity. • Molecular simulations characterized potential interactions and dynamic behaviors within the Topo I–DNA complex. Sophoridine is a quinolizidine-type natural alkaloid with favorable structural modifiability and diverse biological activities. However, the pharmacological potential of sophoridine derivatives originally optimized for insecticidal activity remains largely unexplored. Here, a bioactivity repurposing strategy was applied to investigate the antitumor potential of these derivatives. Screening across multiple cancer cell models identified A549 cells as a sensitive model, and compounds 5 and 9 were selected as active candidates with IC 50 values of 0.124 μM and 1.396 μM, respectively. Topo I-mediated DNA relaxation assays showed that both compounds interfered with the activity of the Topo I–DNA catalytic system in a concentration-dependent manner. Molecular docking, molecular dynamics simulations, and PMF analyses characterized their potential interactions within the Topo I–DNA complex. Preliminary in vivo evaluation suggested inhibitory effects on tumor growth accompanied by tumor tissue necrotic changes following treatment with compounds 5 and 9 . Collectively, these findings highlight the antitumor potential of sophoridine derivatives and suggest that modulation of the Topo I–DNA system may represent one potential mechanism contributing to their biological effects, providing preliminary insights for the further development of sophoridine-based anticancer candidates. A series of sophoridine-based derivatives were systematically evaluated for their antitumor potential. In vitro antiproliferative assays identified compounds 5 and 9 as active candidates against A549 cells, with IC 50 values of 0.124 μM and 1.396 μM, respectively. Topo I-mediated DNA relaxation assays showed that both compounds interfered with the Topo I–DNA catalytic system in a concentration-dependent manner. Molecular docking, molecular dynamics simulations, and PMF analyses further characterized their potential interactions and dynamic behaviors within the Topo I–DNA complex. Preliminary in vivo evaluation suggested that compounds 5 and 9 exhibited inhibitory effects on tumor growth, accompanied by increased tumor necrotic changes. Collectively, these findings indicate that sophoridine derivatives possess promising antitumor potential, while modulation of the Topo I–DNA system may represent one potential mechanism contributing to their biological effects, providing a basis for further optimization and development of sophoridine-based antitumor candidates. Download: Download high-res image (333KB) Download: Download full-size image
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JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY
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2026
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IF 2.2
Yunhan Wang,Xinming Zhang,Fang Fang,Yunyan Chen,Yu Sun
The combination of photothermal therapy and chemotherapy based on nanocarriers is regarded as a promising strategy for enhancing therapeutic efficacy in cancer treatment. Despite the huge progress achieved in the past years, nanocarriers without further specific surface modification can be easily cleared by the immune system thus affecting the therapeutic outcomes. Thus, developing a nanoplatform for active-targeted drug delivery against cancer is of great necessity. Herein, multifunctional lipid-polymer hybrid nanoparticles (abbr. Cet-CINPs) with enhanced long circulation and active targeting ability were constructed by coating the PEGlyated phospholipids and PLGA hybrid core with cetuximab for efficient chemo-photothermal synergistic therapy. Cet-CINPs were prepared through an ultrasonic emulsification method for co-loading irinotecan and indocyanine green. It is demonstrated that Cet-CINPs have spherical morphology with particle size of 119.97 ± 0.93 nm and exhibited excellent dispersion stability in ultrapure water at 4 °C. In vivo experiments showed that compared with conventional drug-loaded nanoparticles without cetuximab modification (CINPs), Cet-CINPs effectively targeted irinotecan transport to Lovo tumor sites. Moreover, upon near-infrared laser irradiation, Cet-CINPs finally accomplished up to 96.71 ± 1.60% tumor inhibition with negligible damage to normal tissues and organs because of the chemo-photothermal combined effect. Therefore, the NIR-activatable and active-targeted lipid-polymer hybrid nanoparticles could provide a precise, efficient, and synergistic method that might have contributed to treatment in colorectal cancer therapy.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Nishtha Thakur,Pablo Mota-Santiago,Shuddhodana,Zaher Judeh
Cochleates offer a structurally robust lipid-based platform for drug delivery but remain limited by structural heterogeneity, aggregation, and poor encapsulation of water-soluble therapeutics due to weak bilayer partitioning. Here, we introduce a cationic surfactant-mediated interfacial engineering strategy to modulate cochleate assembly and enhance encapsulation of water-soluble drugs. Using cetyltrimethylammonium bromide (CTAB) as a model cationic surfactant and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) as the anionic lipid matrix, we demonstrate controlled modulation of bilayer electrostatics and lamellar organization during Ca²⁺-driven cochleate formation. Multimodal characterization using cryo-TEM, FE-SEM, SAXS, FTIR, and DSC indicates that CTAB incorporation occurs in a manner consistent with interfacial bilayer association, without disrupting Ca²⁺-bridged lamellar architecture, preserving the fundamental lamellar repeat spacing while systematically modulating lamellar coherence and colloidal stability. Using irinotecan as a mechanistically stringent model drug with limited intrinsic bilayer affinity, based on its amphiphilic, weakly basic nature and poor loading in unmodified cochleates, CTAB-engineered cochleates exhibit a marked increase in encapsulation efficiency and drug loading, together with improved structural integrity and sustained release under simulated gastrointestinal conditions. These enhancements arise from interactions that favor drug association at the bilayer-aqueous interface rather than deep hydrophobic partitioning, while maintaining cochleate structural organization. This work establishes interfacial electrostatic modulation as an important design principle for cochleate engineering, enabling efficient encapsulation and controlled release of water-soluble therapeutics without compromising structural integrity.
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PHARMACEUTICAL RESEARCH
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2025
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IF 4.3
Zhao Xian,Xu Ruijie,Zhai Yuanyuan,Wang Yi,Zhang Yuxin,Tian Yuan,Xu Fengguo,Zhang Pei
Background Irinotecan (CPT-11) is a standard first-line chemotherapy treatment for colorectal cancer (CRC). However, its clinical application is often comprised by gastrointestinal toxicity and limited therapeutic efficacy. Our previous study has revealed that the combination of Vardenafil (Vard) and Linagliptin (Linag) significantly alleviated CPT-11-induced intestinal toxicity in both in vitro and in vivo models. It remains unclear whether this combination can synergistically enhance the anticancer activity of CPT-11. Methods The in vitro synergism of Vard, Linag, and CPT-11 was assessed using cell viability assays on CRC cell lines, including HCT116, SW620, and HT29. An in vivo xenograft mouse model was established to evaluate the drug efficacy of both the original and liposomal forms of Vard and Linag combined with CPT-11. Additionally, untargeted metabolomics was utilized to explore the potential mechanisms underlying the observed synergistic effects. Results In vitro , the combination of Vard and Linag synergistically enhanced the anticancer activity of CPT-11 in CRC cell lines. In vivo , liposomal formulations of Vard and Linag tended to accumulate at the tumor site, improving drug targeting and synergistically enhancing the anticancer efficacy of CPT-11. Untargeted metabolomics analysis revealed that this synergistic effect was probably mediated through the regulation of lysophospholipid metabolism. Conclusion Liposomal Vard and Linag combined with CPT-11 demonstrated a synergistic anti-CRC effect, offering valuable insights into novel combination therapies in CRC treatment. Graphical
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ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Jiang Huan-guo,Zhan Zhi-kun,Tian Ling-min,Chen Yu-lian,Cai Mei-qun,Ge Guang-bo,Chen Xin,Wei Chuan-liang,Tang Lan
Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg − 1 ·d − 1 , i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα − / − ) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Yuanyuan Zhang,Mingyang Liu,Yifan Zhang,Fengxia Qin,Yuan Tian,Fengguo Xu,Yuxin Zhang,Pei Zhang
The use of irinotecan (CPT-11), a first-line chemotherapeutic agent for colorectal cancer (CRC), is limited by acquired drug resistance and severe adverse effects. It has been found that activation of farnesoid X receptor (FXR) signaling reduced the growth of CRC. Here, we investigated the combination of obeticholic acid (OCA), a well-characterized FXR agonist, with CPT-11 as a potential therapeutic combination for CRC. In vitro experiments demonstrated that the OCA-CPT-11 synergistically inhibited proliferation and migration in FXR-high HT29 and SW620 cells, but exhibited minimal synergy in FXR-low HCT116 and Caco-2 cells. Genetic knockdown of FXR in HT29 cells attenuated the synergistic effects, whereas FXR overexpression in HCT116 cells enhanced them. These findings indicate that the synergistic effect of OCA-CPT-11 depends on basal FXR expression levels, highlighting the need to identify both FXR inducers and agonists. Through literature and database screening, silibinin (SB) and nigakinone (Nig) were identified to upregulate and activate FXR. Both SB-CPT-11 and Nig-CPT-11 exhibited strong synergistic anti-CRC effects in vitro , even under low FXR conditions. Nig achieved synergy with CPT‑11 at lower effective concentrations than SB, so it was prioritized as the lead candidate for in vivo evaluation. Consistently, the Nig-CPT‑11 combination synergistically inhibited the growth of HCT116 subcutaneous xenograft tumors in vivo . Notably. In summary, combining FXR inducers and agonists with CPT-11 offers a promising strategy for the treatment of CRC.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Jin Li,Yaxian Luo,Shuangyang Li,Yuxuan Wang,Tao Qiu,Yixian Wu,Xuankai Fan,Jian Li,Tian Zhang,Di He,Jingyu Zhang,Renjian Hu,Jianguang Zhong,Yongping Hu,Mouyuan Sun
Tumor heterogeneity remains a major barrier to effective cancer therapy, driving the need for novel biomarkers and targeted strategies. A bibliometric analysis underscored the lack of a systematic pan-cancer study of PLAUR. By integrating functional experiments, multi-omics analyses, and machine learning, we systematically investigated urokinase-type plasminogen activator receptor (PLAUR) across malignancies. PLAUR overexpression was observed in 10 cancer types, with significant prognostic value in 7 of these. Epigenetic analysis revealed its association with specific methylation patterns. Functionally, PLAUR drives malignant phenotypes by mediating tumor-cancer-associated fibroblast (CAF) crosstalk, remodeling the immunosuppressive microenvironment, and is implicated in therapy resistance. We identified four FDA-approved drugs (5-Fluorouracil, Irinotecan, Talazoparib, Gemcitabine) that may have potential binding affinity to PLAUR through in silico analyses, and in vitro functional assays using the human tongue squamous cell carcinoma cell line CAL-27. We further validated that Irinotecan can significantly reduce PLAUR expression and suppress malignant phenotypes (including survival, proliferation, migration, and invasion), which consolidates the preliminary findings from in silico analyses. Furthermore, we characterized peroxidasin (PXDN) as a core PLAUR-interacting hub and propose five candidate drugs (IGF1R-3801, Taselisib, Dasatinib, 5-Fluorouracil, and Alpelisib) for a synergistic dual-target strategy. Our work establishes PLAUR as a pivotal pan-cancer biomarker and potential therapeutic target, providing a rational framework for precision oncology.
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ACS Nano
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2026
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IF 17.3
Mengxi Xiang,Cheng Zhou,Chundong Yao,Jia Liu,Lin Wang,Zheng Wang
Irinotecan is a widely used chemotherapeutic agent for the treatment of advanced and metastatic colorectal cancer (CRC). However, its clinical application remains unsatisfactory due to its side effects and limited efficacy. Here, we first demonstrate that irinotecan promotes liver metastasis in CRC by inducing chemotherapy-related steatohepatitis, which is an understudied side effect of irinotecan. To abrogate the prometastatic effect of irinotecan, we employ indole-3-carbinol (I3C), an aryl hydrocarbon receptor (AHR) agonist, to develop a self-assembled nanomedicine (termed NICER). NICER abolishes liver metastasis driven by irinotecan-induced steatohepatitis through activating the AHR/CPT1A axis and promoting fatty acid oxidation of hepatocytes. Importantly, NICER also significantly potentiated the antitumor effect of irinotecan. It markedly enhances cellular uptake of irinotecan via caveolin-dependent endocytosis, enabling direct delivery to the endoplasmic reticulum (ER) to induce lethal ER stress. Meanwhile, I3C encapsulated in NICER inhibits glycolysis by activation of AHR. In subcutaneous and liver metastatic CRC models, NICER demonstrates potent antitumor efficacy, reducing the tumor burden by 74.6% and 96.2%, respectively, while also exhibiting good biosafety. In summary, this work synergistically abrogates the prometastatic adverse effect of irinotecan and enhances its antitumor efficacy, presenting a promising strategy to potentiate irinotecan-based chemotherapies.
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Acta Biomaterialia
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2022
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IF 10.633
Lanhong Su,Wen Pan,Xiangxia Li,Xingyu Zhou,Xiaopeng Ma,Yuanzeng Min
Chemotherapy has become a popular combination strategy to improve the response rate of immunotherapy since certain chemotherapeutic drugs kill tumor cells by an immunogenic cell death (ICD) pathway, which activates antitumor immune responses. Unfortunately, the synergistic effect of chemoimmunotherapy can be impaired due to the toxicities of chemotherapeutic agent-induced lymphatic depletion and immunosuppression. In this study, we present an approach to improve immunotherapy by using tumor RNA nanoparticles (RNA-NPs) where RNA is directly extracted from chemotherapy-treated cancer cells and then condensed by protamine via electrostatic interactions to form complexes. Such RNA-NPs can be effectively taken up by dendritic cells (DCs) in the draining lymph nodes after subcutaneous injection. Compared with noninduced tumor RNA nanoparticles (N-RNA-NPs), chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) can significantly promote DC maturation and stimulate a stronger immune response against established CT-26 colon carcinoma. Besides, C-RNA-NPs can improve the efficacy of immune checkpoint blockade (ICB) therapy by facilitating the infiltration of intratumoral T cells and increasing the ratio of CD8 + T cells to regulatory T cells (Tregs). More importantly, the synergistic effect of chemoimmunotherapy is also enhanced by treatment with C-RNA-NPs. Statement of significance Although immune checkpoint blockade therapy has been demonstrated to be effective in some advanced cancers, the low response rate has significantly limited its clinical application. To address this issue, a new strategy for improving cancer immunotherapy using chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) is developed in this work. The proposed C-RNA-NPs could be captured by dendritic cells, which were then stimulated to the maturation status to initiate an anticancer immune response. Furthermore, the response rate to immunotherapy was significantly increased by promoting intratumoral T-cell infiltration and elevating the intratumoral ratio of CD8 + T cells to regulatory T cells after treatment with C-RNA-NPs. Therefore, C-RNA-NPs have the potential to improve cancer immunotherapy.
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Acta Biomaterialia
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2022
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IF 10.633
Lanhong Su,Yuhao Hao,Rui Li,Wen Pan,Xiaopeng Ma,Jianping Weng,Yuanzeng Min
Immune checkpoint blockade (ICB) therapy has shown promising antitumor effects, but its immune response rate remains unsatisfactory. In recent years, chemotherapy has been proven to have synergistic effects with ICB therapy because some chemotherapeutic agents can enhance the immunogenicity of tumor cells by inducing immunogenic cell death (ICD). However, it cannot be ignored that chemotherapy often shows limited therapeutic efficacy due to high cytotoxicity, drug resistance, and some other side effects. Herein, we report a strategy to improve cancer immunotherapy by utilizing red blood cell-based vaccines (RBC-vaccines) where chemotherapy-induced tumor antigens (cAgs) are anchored onto red blood cells (RBCs) via the EDC/NHS-mediated amine coupling reaction. In this work, RBC-vaccines administered subcutaneously are primarily devoured by dendritic cells (DCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment by increasing the infiltration of intratumoral CD8 + and CD4 + T cells and elevating the intratumoral ratio of CD8 + T cells to regulatory T cells in the CT-26 colon cancer model. Finally, based on the rejection of tumor rechallenge in cured mice, the combination therapy of RBC-vaccines and αPD-1 can induce the expansion of memory T cells and thereby establish a long-term antitumor immune response. Taken together, the proposed RBC-vaccines have great potential to improve chemoimmunotherapy. Statement of significance Immunotherapy, especially immune checkpoint blockade therapy, has made great contributions to the treatment of some advanced cancers. Unfortunately, the great majority of patients with cancer do not benefit from immunotherapy. To enhance the response rate of immunotherapy, we developed red blood cell-based vaccines (RBC-vaccines) against cancers where antigens were harvested from chemotherapy-treated cancer cells and then attached to erythrocytes via covalent surface modification. Such RBC-vaccines could provide a wide variety of tumor antigens and damage-associated molecular patterns without the use of any extra ingredients to trigger a stronger antitumor immune response. More importantly, the combination of RBC-vaccines with PD-1 blockade could significantly improve the efficacy of cancer immunotherapy and induce durable antitumor immunity.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 12
·6597
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IF 6.208
Yaowei Guo,Jin Liu,Qinglin Tang,Cuicui Li,Yanying Zhang,Yao Wang,Yanxin Wang,Yupeng Bi,Christopher D. Snow,Matt J. Kipper,Laurence A. Belfiore,Jianguo Tang
The clinical use of anticancer drugs necessitates new technologies for their safe, sensitive, and selective detection. In this article, lanthanide (Eu3+and Tb3+)-loaded γ-cyclodextrin nano-aggregates (ECA and TCA) are reported, which sensitively detects the anticancer drug irinotecan by fluorescence intensity changes. Fluorescent lanthanide (Eu3+and Tb3+) complexes exhibit high fluorescence intensity, narrow and distinct emission bands, long fluorescence lifetime, and insensitivity to photobleaching. However, these lanthanide (Eu3+and Tb3+) complexes are essentially hydrophobic, toxic, and non-biocompatible. Lanthanide (Eu3+and Tb3+) complexes were loaded into naturally hydrophilic γ-cyclodextrin to form fluorescent nano-aggregates. The biological nontoxicity and cytocompatibility of ECA and TCA fluorescent nanoparticles were demonstrated by cytotoxicity experiments. The ECA and TCA fluorescence nanosensors can detect irinotecan selectively and sensitively through the change of fluorescence intensity, with detection limits of 6.80 μM and 2.89 μM, respectively. ECA can safely detect irinotecan in the cellular environment, while TCA can detect irinotecan intracellularly and is suitable for cell labeling.Keywords:lanthanide (Eu3+, Tb3+) complex;γ-cyclodextrin;nano-aggregate;sensing;anticancer drug;irinotecan
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Metabolites
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2022
·Vol. 12
·期 6
·494
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IF 5.581
Bo Lv,Ruijie Xu,Xinrui Xing,Chuyao Liao,Zunjian Zhang,Pei Zhang,Fengguo Xu
The accumulation of cancer metabolomics data in the past decade provides exceptional opportunities for deeper investigations into cancer metabolism. However, integrating a large amount of heterogeneous metabolomics data to draw a full picture of the metabolic reprogramming and to discover oncometabolites of certain cancers remains challenging. In this study, a tumor barcode constructed based upon existing metabolomics “big data” using the Bayesian vote-counting method is proposed to identify oncometabolites in colorectal cancer (CRC). Specifically, a panel of oncometabolites of CRC was generated from 39 clinical studies with 3202 blood samples (1332 CRC vs. 1870 controls) and 990 tissue samples (495 CRC vs. 495 controls). Next, an oncometabolite-protein network was constructed by combining the tumor barcode and its involved proteins/enzymes. The effect of anti-cancer drugs or drug combinations was then mapped into this network by the random walk with restart process. Utilizing this network, potential Irinotecan (CPT-11)-sensitizing agents for CRC treatment were discovered by random forest and Xgboost. Finally, a compound named MK-2206 was highlighted and its synergy with CPT-11 was validated on two CRC cell lines. To summarize, we demonstrate in the present study that the metabolomics “big data”-based tumor barcodes and the subsequent network analyses are potentially useful for drug combination discovery or drug repositioning.Keywords:tumor barcode;Bayesian vote-counting;colorectal cancer;metabolomics;drug combination;Irinotecan
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