Publications by authors named "Su Zeng"

335 Publications

Plasma-metabolite-based machine learning is a promising diagnostic approach for esophageal squamous cell carcinoma investigation.

J Pharm Anal 2021 Aug 28;11(4):505-514. Epub 2020 Nov 28.

The Cancer Research Institute, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.

The aim of this study was to develop a diagnostic strategy for esophageal squamous cell carcinoma (ESCC) that combines plasma metabolomics with machine learning algorithms. Plasma-based untargeted metabolomics analysis was performed with samples derived from 88 ESCC patients and 52 healthy controls. The dataset was split into a training set and a test set. After identification of differential metabolites in training set, single-metabolite-based receiver operating characteristic (ROC) curves and multiple-metabolite-based machine learning models were used to distinguish between ESCC patients and healthy controls. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were performed to investigate the prognostic significance of the plasma metabolites. Finally, twelve differential plasma metabolites (six up-regulated and six down-regulated) were annotated. The predictive performance of the six most prevalent diagnostic metabolites through the diagnostic models in the test set were as follows: arachidonic acid (accuracy: 0.887), sebacic acid (accuracy: 0.867), indoxyl sulfate (accuracy: 0.850), phosphatidylcholine (PC) (14:0/0:0) (accuracy: 0.825), deoxycholic acid (accuracy: 0.773), and trimethylamine N-oxide (accuracy: 0.653). The prediction accuracies of the machine learning models in the test set were partial least-square (accuracy: 0.947), random forest (accuracy: 0.947), gradient boosting machine (accuracy: 0.960), and support vector machine (accuracy: 0.980). Additionally, survival analysis demonstrated that acetoacetic acid was an unfavorable prognostic factor (hazard ratio (HR): 1.752), while PC (14:0/0:0) (HR: 0.577) was a favorable prognostic factor for ESCC. This study devised an innovative strategy for ESCC diagnosis by combining plasma metabolomics with machine learning algorithms and revealed its potential to become a novel screening test for ESCC.
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http://dx.doi.org/10.1016/j.jpha.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424362PMC
August 2021

Feature, Function, and Information of Drug Transporter Related Databases.

Drug Metab Dispos 2021 Aug 23. Epub 2021 Aug 23.

College of Pharmaceutical Sciences, Zhejiang University, China

With the rapid progress in pharmaceutical experiments and clinical investigations, extensive knowledge of drug transporters (DTs) has accumulated, which is valuable data for the understanding of drug metabolism and disposition. However, such data is largely dispersed in the literature, which hampers its utility and significantly limits its possibility for comprehensive analysis. A variety of databases have, therefore, been constructed to provide DT-related data, and they were reviewed in this study. First, several knowledge bases providing data regarding clinically important drugs and their corresponding transporters were discussed, which constituted the most important resources of DT-centered data. Second, some databases describing the general transporters and their functional families were reviewed. Third, various databases offering transporter information as part of their entire data collection were described. Finally, customized database functions that are available to facilitate DT-related research were discussed. This review provided an overview of the whole collection of DT-related databases, which might facilitate research on precision medicine and rational drug use. A collection of well-established databases related to DTs were comprehensively reviewed, which were organized according to their importance in drug ADME research. These databases could collectively contribute to the research on rational drug use.
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http://dx.doi.org/10.1124/dmd.121.000419DOI Listing
August 2021

Metastatic colorectal cancer: Perspectives on long non-coding RNAs and promising therapeutics.

Eur J Pharmacol 2021 Oct 22;908:174367. Epub 2021 Jul 22.

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address:

Metastatic colorectal cancer (mCRC) has long been lethal despite the continuous efforts of researchers worldwide to discover and improve therapeutic regimens. Thanks to the emergence of long non-coding RNAs (lncRNAs), which has strongly reshaped our inherent perspectives on the pathophysiological patterns of disease, research in the field has been reinvigorated. Here, we focus on current understanding of the modes of action of lncRNAs, and review their regulatory roles in metastatic colorectal cancer, and discuss correlated potential lncRNA-based therapeutics. All of the discussed studies share clear and promising perspectives on future diagnostic and therapeutic remedies for metastatic colorectal cancer.
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http://dx.doi.org/10.1016/j.ejphar.2021.174367DOI Listing
October 2021

L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity.

Toxicology 2021 07 9;459:152853. Epub 2021 Jul 9.

Laboratory of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China. Electronic address:

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 μM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.
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http://dx.doi.org/10.1016/j.tox.2021.152853DOI Listing
July 2021

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization.

Cell Death Dis 2021 05 24;12(6):532. Epub 2021 May 24.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China.

Human intestinal peptide transporter PEPT1 is commonly repressed in human colorectal cancer (CRC), yet its relationship with sensitivity to the common CRC treatment ubenimex has not previously been elucidated. In this study, we confirmed PEPT1 suppression in CRC using real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic pathways involved using bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays. We found that PEPT1 transcriptional repression was due to both DNMT1-mediated DNA methylation of the proximal promoter region and HDAC1-mediated histone deacetylation, which blocked P300-mediated H3K18/27Ac at the PEPT1 distal promoter. Finally, the effects of the epigenetic activation of PEPT1 on the CRC response to ubenimex were evaluated using sequential combination therapy of decitabine and ubenimex both in vitro and in xenografts. In conclusion, epigenetic silencing of PEPT1 due to increased DNMT1 and HDAC1 expression plays a vital role in the poor response of CRC to ubenimex.
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http://dx.doi.org/10.1038/s41419-021-03814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144210PMC
May 2021

Identification of the key target profiles underlying the drugs of narrow therapeutic index for treating cancer and cardiovascular disease.

Comput Struct Biotechnol J 2021 21;19:2318-2328. Epub 2021 Apr 21.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets. However, the association between the drug therapeutic index and the related disease has not been dissected, which is important for revealing the NTI drug mechanism and optimizing drug design. Therefore, in this study, two classes of disease (cancers and cardiovascular disorders) with the largest number of NTI drugs were selected, and the target property of the corresponding NTI drugs was analyzed. By calculating the biological system profiles and human protein-protein interaction (PPI) network properties of drug targets and adopting an AI-based algorithm, differentiated features between two diseases were discovered to reveal the distinct underlying mechanisms of NTI drugs in different diseases. Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease.
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http://dx.doi.org/10.1016/j.csbj.2021.04.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105181PMC
April 2021

Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma.

Biomedicines 2021 Apr 30;9(5). Epub 2021 Apr 30.

Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Cancer Center of Zhejiang University, Hangzhou 310058, China.

Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the expression of MRP4. However, regulation of MRP4 by circular RNA (circRNA) is yet to be elucidated. In this study, MRP4 was significantly upregulated in hepatocellular carcinoma (HCC) tissues compared to the adjacent noncancerous tissues. Computational prediction, luciferase reporter assay and miRNA transfection were used to investigate the interaction between miRNAs and MRP4. miR-124-3p and miR-4524-5p reduced the expression of MRP4 at the protein but not mRNA level. Circular RNA in vivo precipitation and luciferase reporter assays demonstrated that circHIPK3, as a competitive endogenous RNA, binds with miR-124-3p and miR-4524-5p. Further, knockdown of circHIPK3 resulted in downregulation of MRP4 protein, whereas cotransfection of circHIPK3-siRNA and miR-124-3p or miR-4524-5p inhibitors restored its expression. In conclusion, we report that miR-4524-5p downregulates the expression of MRP4 and circHIPK3 regulates MRP4 expression by sponging miR-124-3p and miR-4524-5p for the first time. Our results may provide novel insights into the prevention of MRP4-related proliferation and multiple drug resistance in HCC.
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http://dx.doi.org/10.3390/biomedicines9050497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147194PMC
April 2021

Stability and compatibility of methotrexate and dexamethasone in 0.9% sodium chloride for intrathecal injection.

Authors:
Fan Xu Su Zeng

Pak J Pharm Sci 2020 Nov;33(6):2477-2481

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

The stability of a mixture of methotrexate and dexamethasone sodium phosphate in 0.9% sodium chloride for intrathecal (IT) injection was assessed. To simulate the clinically used concentrations of the admixtures, 2mL of 0.9% sodium chloride was added into each of two vials of methotrexate. Both solution mixtures were then transferred into an intrathecal injector. A vial of dexamethasone sodium phosphate (5mg in 1mL) was subsequently added directly to the injector to obtain a mixture of 2mg/mL methotrexate and 1mg/mL dexamethasone. Subsequently, stability as assessed by visual evaluation of color changes, regular pH monitoring, monitoring of changes in particulate contents and drug concentrations in the admixture, and detection of impurities with HPLC- UV-TOF/MS before and after mixing. The results showed that admixtures were clear, no color changes were observed and the pH value remained stable under normal fluorescent room light. The >25-μm and >10-μm particulate content levels were low and within specification limits. The concentrations of methotrexate and dexamethasone exhibited no significant changes. Impurity peaks before and after mixing were not increased and no new degradation products were detected after mixing. Methotrexate and dexamethasone sodium phosphate did not affect each other's stability.
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November 2020

Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma.

Biochem Pharmacol 2021 06 8;188:114546. Epub 2021 Apr 8.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, China. Electronic address:

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The failure of chemotherapy in HCC patients is partly due to inadequate intracellular drug accumulation caused by abnormally expressed drug transporters. Human organic anion transporter 2 (hOAT2), a transporter mainly expressed in liver and kidney, is responsible for uptake of various antineoplastic drugs such as 5-fluorouracil (5-FU). Among 32 pairs of human HCC samples, we preliminarily found that OAT2 was suppressed in HCC tissues compared with matched tumor-adjacent tissues at both mRNA and protein levels, which resulted in 5-FU resistance in HCC. However, the epigenetic regulatory mechanisms of OAT2 downregulation have not been investigated. In this study, we first proved it was histone hypoacetylation rather than DNA hypermethylation that participated in transcriptional repression of OAT2 in two HCC cell lines (BEL-7402 and SMMC-7721). In general, there were two pathways confirmed using tissues and cells: 1) Increased histone deacetylase sirtuin 7 (SIRT7) mediated loss of histone 3 lysine 18 acetylation (H3K18ac) at the promoter of OAT2 and inhibited its transcription. 2) More histone deacetylase 7 (HDAC7) instead of lysine acetyltransferase 8 (KAT8) enrichment at the promoter of OAT2 led to low levels of histone 4 lysine 16 acetylation (H4K16ac). Further, we found that histone deacetylases inhibitor vorinostat (SAHA) could reverse histone hypoacetylation state to activate OAT2 transcription and enhance uptake of classic OAT2 substrate zidovudine. Therefore, we evaluated the effect of combining SAHA and 5-FU and the results demonstrated that SAHA could sensitize HCC cells to 5-FU. Collectively, we proposed such a combination treatment to overcome 5-FU resistance in HCC from the perspective of epigenetically restoring OAT2.
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http://dx.doi.org/10.1016/j.bcp.2021.114546DOI Listing
June 2021

The Strategy of Conditionally Replicating Adenovirus-Mediated PreS2 Mini-Antibody Expression Has Dual Effects of Inhibiting HBV Infection and Preventing Hepatocellular Carcinoma.

Cancer Manag Res 2021 24;13:1869-1876. Epub 2021 Feb 24.

Center of Thyroid and Parathyroid, Department of Thyroid, Parathyroid, Breast and Hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.

Aim: To investigate the inhibitory effect of hepatitis B virus (HBV) preS2 mini-antibody (mPreS2) against HBV infection, HBV-associated liver injury and HBV-associated hepatic carcinogenesis.

Methods: A recombinant adenovirus vector with the human survivin promoter and mPreS2 gene, Ad5SVP-mPreS2, was constructed. Fluorescence microscopy examination and TCID 50 analysis were utilized to determine the specific proliferation of recombinant adenovirus in liver cancer cells. Western blot analysis was used to determine the mPreS2 expression levels. Enzyme-linked immunosorbent assay (ELISA) was used to examine HBsAg levels to evaluate the inhibitory effect of mPreS2 against HBV infection. The protective effects on hepatic function and preventive effects against hepatic carcinogenesis of Ad5SVP-mPreS2 were studied in diethylnitrosamine (DEN)-treated HBV transgenic Imprinting Control Region mice.

Results: The recombinant adenovirus regulated by the human survivin promoter proliferated exclusively in liver cancer cells rather than normal liver cells. The expression levels of mPreS2 were increased in liver cancer cells compared with normal liver cells, and mPreS2 could be used to recognize liver cells from HBV transgenic mice. ELISA showed that HBsAg levels were decreased in the group treated with Ad5SVP-mPreS2. Ad5SVP-mPreS2 had a protective effect on hepatic function in a DEN-induced liver injury model because of lower serum levels of alanine transaminase and aspartate transaminase. Additionally, HBV transgenic mice treated with Ad5SVP-mPreS2 had fewer and smaller cancerous nodes after induction with DEN than untreated mice.

Conclusion: Conditionally replicating adenovirus-mediated mPreS2 expression inhibited HBV infection and had an inhibitory effect on liver injury and hepatocellular carcinogenesis in HBV transgenic mice.
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http://dx.doi.org/10.2147/CMAR.S298331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917352PMC
February 2021

Tissue-based metabolomics reveals metabolic biomarkers and potential therapeutic targets for esophageal squamous cell carcinoma.

J Pharm Biomed Anal 2021 Apr 5;197:113937. Epub 2021 Feb 5.

Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Banshandong Road#1, Hangzhou, Zhejiang Province, 310022, China; Cancer Hospital of the University of Chinese Academy of Sciences, Banshandong Road#1, Hangzhou, Zhejiang Province, 310022, China; Zhejiang Cancer Hospital, Banshandong Road#1, Hangzhou, Zhejiang Province, 310022, China. Electronic address:

Prognosis for esophageal squamous cell carcinoma (ESCC) is poor, so it is essential to develop a more complete understanding of the disease. The purpose of this study was to explore metabolic biomarkers and potential therapeutic targets for ESCC. An ultra-high-performance liquid chromatography coupled with high resolution mass (UPLC/MS)-based metabolomic analysis was performed in 141 ESCC cancerous tissue samples and 70 non-cancerous counterparts. The results showed that 41 differential metabolites were annotated in the training set, and 37 were validated in the test set. Single-metabolite-based receiver operating characteristic (ROC) curves as well as metabolite-based machine learning models, including Partial Least Squares (PLS), Support Vector Machine (SVM), and Random Forest (RF), were investigated for cancerous and non-cancerous tissue classification. Six most prevalent diagnostic metabolites-adenylsuccinic acid, UDP-GalNAc, maleylacetoacetic acid, hydroxyphenylacetylglycine, galactose, and kynurenine-showed testing predictive accuracies of 0.89, 0.95, 0.97, 0.89, 0.84, and 0.84, respectively. Moreover, the metabolite-based models (PLS, SVM, and RF) had testing predictive accuracies of 0.95, 0.95, and 1.00, respectively. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis demonstrated that 2-hydroxymyristoylcarnitine (HR: 0.55, 95 % CI: 0.32 to 0.92), 3-hydroxyhexadecanoylcarnitine (HR: 0.49, 95 % CI: 0.29 to 0.83), and 2,3-Dinor-TXB1 (HR: 0.56, 95 % CI: 0.33 to 0.95) to be significantly associated with OS. Based on the observation of accumulation in amino acids, immunohistochemistry (IHC) staining revealed that the amino acid transporters SLC7A5/LAT1, SLC1A5/ASCT2, and SLC16A10/MCT10 were up-regulated in ESCC cancerous tissues when compared to non-cancerous equivalents. Consistently, the same panel of amino acids were downregulated in cells with SLC1A5 knockdown. Herein, it is concluded that this study not only identified several metabolites with diagnostic and/or prognostic value, but also provided accurate metabolite-based prediction models for ESCC tissue classification. Furthermore, the three up-regulated amino acid transporters were identified as potential therapeutic targets for ESCC, especially SLC1A5.
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http://dx.doi.org/10.1016/j.jpba.2021.113937DOI Listing
April 2021

miR-224-5p Contained in Urinary Extracellular Vesicles Regulates PD-L1 Expression by Inhibiting Cyclin D1 in Renal Cell Carcinoma Cells.

Cancers (Basel) 2021 Feb 4;13(4). Epub 2021 Feb 4.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

The abundant miRNAs in urinary extracellular vesicles (EVs) represent ideal reservoirs for biomarker discovery, especially in renal cell carcinoma (RCC). However, the content and biological functions of microRNAs contained in urinary EVs in RCC remain ambiguous. In this study, urinary EVs were isolated and characterized from RCC patients and healthy volunteers. Differentially expressed microRNAs in urinary EVs were screened by small RNA sequencing. The target gene and biological functions of selected microRNAs were investigated through multifaceted methods. Results indicated that miR-224-5p was significantly upregulated in urinary EVs of RCC patients compared to healthy volunteers. The overexpression of miR-224-5p inhibited RCC cell proliferation and induced cell cycle arrest. The gene encoding cyclin D1 was identified as a direct target of miR-224-5p via prediction and validation. Moreover, the invasive and metastatic abilities of RCC cells were enhanced by miR-224-5p. Interestingly, miR-224-5p also increased the stability of PD-L1 protein by inhibiting . This effect could be transmitted via EVs and further promoted the resistance of RCC cells to T cell-dependent toxicity. In summary, urinary EVs containing miR-224-5p were identified as a potential biomarker in RCC. Regulation of PD-L1 protein expression by miR-224-5p through suppressing elucidates new roles of miR-224-5p in RCC progression.
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http://dx.doi.org/10.3390/cancers13040618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913995PMC
February 2021

The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer.

Expert Opin Drug Metab Toxicol 2021 Mar 22;17(3):291-306. Epub 2021 Feb 22.

Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Introduction: Multi-drug resistance (MDR) is a hindrance toward the successful treatment of cancers. The primary mechanism that gives rise to acquired chemoresistance is the overexpression of adenosine triphosphate-binding cassette (ABC) transporters. The dysregulation of non-coding RNAs (ncRNAs) is a widely concerned reason contributing to this phenotype.

Areas Covered: In this review, we describe the role of intracellular and exosomal ncRNAs including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ABC transporters-induced tumor MDR. Meanwhile, we will introduce the potential therapeutic strategies which reverse MDR in terms of reducing the expression of ABC transporters targeting ncRNAs, like nucleic acid delivery with nanoparticles as well as miRNAs-targeted small molecular compounds.

Expert Opinion: The dysregulated ncRNAs-mediated overexpression of ABC transporters in chemo-resistant cancer is not negligible. Finding out the underlying mechanism may provide a theoretical basis for clinical therapy of cancer MDR, and the emergence of new approaches for gene therapy targeting ncRNAs to suppress ABC transporters makes reversing cancer MDR possible despite its clinical application requires further investigations. Also, the discovered ncRNAs regulating ABC transporters in chemo-resistant cancers are just a tip of the iceberg of the genetic transcripts, especially for circRNAs, which justify more concern. MDR, multi-drug resistance; ABC, adenosine triphosphate-binding cassette; NcRNAs, non-coding RNAs; MiRNAs, microRNAs; LncRNAs, long non-coding RNAs; CircRNAs, circular RNAs; CeRNAs, competing endogenous RNAs; 3'UTR, 3'-untranslated regions; SLC, solute carrier; ABCB1/MDR1, ABC subfamily B member 1; ABCG2/BCRP, ABC subfamily G member 2; ABCCs/MRPs, ABC subfamily C 1 to 12; DLL1: Delta-like protein 1; DTX, docetaxel; DOX/ADM/ADR, doxorubicin/adriamycin; PTX, paclitaxel; VBL, vinblastine; VCR, vincristine; MTX, methotrexate; CDDP/DDP, cisplatin/cis-diaminedichloroplatinum; OXA/L-OHP, oxaliplatin; TMZ, temozolomide; 5-FU, 5-fluorouracil; MTA, pemetrexed; NSCLC, non-small cell lung carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal carcinoma; RB, retinoblastoma; RCC, renal cell carcinoma; OS, osteosarcoma; PDAC, pancreatic ductal adenocarcinoma; TNBC, triple-negative breast cancer.
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http://dx.doi.org/10.1080/17425255.2021.1887139DOI Listing
March 2021

The characterisation of the metabolism and transport of 6-hydroxykynurenic acid, an important constituent of extracts.

Xenobiotica 2021 May 8;51(5):513-521. Epub 2021 Feb 8.

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Cancer Center of Zhejiang University, College of Pharmaceutical Sciences, Hangzhou, PR China.

6-Hydroxykynurenic acid (6-HKA) is a nitrogen-containing phenolic acid compound in leaves. The pharmacological activities of 6-HKA have been reported and shown that 6-HKA has the potential to become a therapeutic drug and may play an important role in the treatment of nervous system diseases. However, there are few studies on the drug metabolism and transport of 6-HKA. The aim of this study is to investigate the metabolism of 6-HKA and its interaction with multiple important drug transporters.The metabolism experiments in the present study demonstrate that 6-HKA might not undergo phase-I or phase-II metabolism in hepatic microsomes/S9 of rats. In addition, some drug transporters, including OAT1/3, OCT2, MDR1, OATP1B1, MATE1/2K and OCTN2, were investigated. The cellular uptake assays indicate that 6-HKA exhibits inhibition to the transport of classical substrates mediated by OAT3, OCT2, MATE2K and OCTN2 but has no significant effect on the transport of substrates mediated by MDR1, OAT1, OATP1B1 or MATE1. Further investigation of cellular accumulation assays shows that 6-HKA might be the substrate of OAT3, but not OCT2 or OCTN2. The bidirectional transport study suggests that 6-HKA is not a substrate of MDR1.The information about the metabolism of 6-HKA and the interaction between 6-HKA and some transporters will help us to better understand the pharmacokinetic properties of 6-HKA and provide reference for its pharmacodynamics, DDIs and drug-food interactions studies.
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http://dx.doi.org/10.1080/00498254.2021.1881654DOI Listing
May 2021

Development of a UHPLC-MS/MS method for the quantification of ilaprazole enantiomers in rat plasma and its pharmacokinetic application.

J Pharm Anal 2020 Dec 17;10(6):617-623. Epub 2019 Sep 17.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

In Korea and China, ilaprazole is a widely used proton pump inhibitor in the treatment of gastric ulcers. In this study, a specific and sensitive LC-MS/MS method has been developed and validated for the quantification of ilaprazole enantiomers in the rat plasma, using -lansoprazole as the internal standard. The enantioseparation was achieved on a CHIRALPAK AS-RH column (4.6 mm × 150 mm, i.d. 5 μm), with a mobile phase composed of 10 mM ammonium acetate aqueous solution and acetonitrile (60:40, ), at a flow-rate of 0.5 mL/min. The method was validated over the concentration range of 0.5-300 ng/mL for both, - and -ilaprazole. The lower limit of quantification was 0.5 ng/mL for both enantiomers. The relative standard deviation (RSD) of intra- and inter-day precision of -ilaprazole and -ilaprazole was less than 10.9%, and the relative error accuracy (RE) ranged from -0.5%-2.0%. Finally, the method was successfully evaluated in rats in a stereoselective pharmacokinetic study of the ilaprazole racemate.
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http://dx.doi.org/10.1016/j.jpha.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775851PMC
December 2020

Effects of rhein and Rheum palmatum L. extract on the pharmacokinetics and tissue distribution of aristolochic acid I and its demethylated metabolite in rats.

J Ethnopharmacol 2021 Mar 1;267:113537. Epub 2020 Nov 1.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China. Electronic address:

Ethnopharmacological Relevance: Aristolochic acid nephropathy (AAN) is a kidney disease caused by the administration of plants containing aristolochic acids (AAs). Aristolochic acid I (AAI) is the main toxic component in AAs. Organic anion transporters (OATs) 1 and 3 mediate the renal uptake of AAI, which is related to AAN. In our previous study, we found that anthraquinones derived from the herbal medicine Rheum palmatum L. (RP) inhibited both OAT1 and OAT3, with rhein exhibiting the greatest potency among the components.

Aim Of The Study: This study aimed to investigate the effects of rhein and RP extract on the pharmacokinetics and tissue distribution of AAI and its demethylated metabolite (8-hydroxy-aristolochic acid I [AAIa]) in rats.

Materials And Methods: Rhein and RP extract were used as OAT inhibitors, and AAI was used as the toxic substrate. The pharmacokinetics and tissue distribution of AAI and AAIa in rats following the intravenous injection of AAI (10 mg/kg) in the presence and absence of rhein (100 mg/kg) or RP extract (5 g crude drug/kg) were investigated.

Results: Co-administration with rhein increased AUC of AAI and AAIa by 39 and 44%, respectively. However, the renal level of AAI was decreased to 50, 42, and 58% of those in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively, and the renal level of AAIa was decreased to 58, 57, and 61% of the level in rats treated with AAI alone, respectively, at these time points. In the RP extract co-administration group, AAI and AAIa plasma exposure was not significantly increased, but renal accumulation of AAI was decreased to 63, 58, and 68% of that in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively. In addition, renal accumulation of AAIa was decreased to 74, 70, and 70% of that in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively.

Conclusions: This study indicated that co-administration with rhein significantly increased the plasma exposure of AAI and AAIa while decreased their renal accumulation in rats. RP extract reduced the renal accumulation of AAI and AAIa, but have no significant effect on their plasma exposure levels in rats.
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http://dx.doi.org/10.1016/j.jep.2020.113537DOI Listing
March 2021

Recent progress in the molecular imaging of therapeutic monoclonal antibodies.

J Pharm Anal 2020 Oct 8;10(5):397-413. Epub 2020 Aug 8.

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Therapeutic monoclonal antibodies have become one of the central components of the healthcare system and continuous efforts are made to bring innovative antibody therapeutics to patients in need. It is equally critical to acquire sufficient knowledge of their molecular structure and biological functions to ensure the efficacy and safety by incorporating new detection approaches since new challenges like individual differences and resistance are presented. Conventional techniques for determining antibody disposition including plasma drug concentration measurements using LC-MS or ELISA, and tissue distribution using immunohistochemistry and immunofluorescence are now complemented with molecular imaging modalities like positron emission tomography and near-infrared fluorescence imaging to obtain more dynamic information, while methods for characterization of antibody's interaction with the target antigen as well as visualization of its cellular and intercellular behavior are still under development. Recent progress in detecting therapeutic antibodies, in particular, the development of methods suitable for illustrating the molecular dynamics, is described here.
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http://dx.doi.org/10.1016/j.jpha.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591813PMC
October 2020

Formation of an Unprecedented Impurity during CE-SDS Analysis of a Recombinant Protein.

Pharm Res 2020 Oct 23;37(11):228. Epub 2020 Oct 23.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Purposes: The main purposes of this article are to describe an unprecedented phenomenon in which significant amount of a shoulder peak impurity was observed during normal non-reducing capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) analysis of a recombinant fusion protein X, and to evaluate the root cause for this phenomenon.

Methods: A series of experiments were conducted to study the nature of this degradation. Effects of iodoacetamide (IAM), heating temperature, duration, and SDS on the formation of this specific impurity were evaluated using a variety of characterization techniques.

Results: The formation of the impurity as observed in CE-SDS was actually due to alkylation of lysine and serine residues with IAM, as confirmed by peptide mapping and LC-MS/MS, which increased the molecular weight and therefore decreased the electrophoretic mobility. The amount of impurity was also strongly dependent on sample preparation conditions including the presence or absence of SDS.

Conclusions: Our study clearly suggested that even though IAM has been used extensively as an alkylation reagent in the traditional non-reducing CE-SDS analysis of monoclonal antibodies and other proteins, alkylation with IAM could potentially lead to additional impurity peak, and therefore complicating analysis. Therefore, before performing CE-SDS and other analyses, the effects of sample preparation procedures on analytical results must be evaluated. For protein X, IAM should be excluded for CE-SDS analysis.
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http://dx.doi.org/10.1007/s11095-020-02947-0DOI Listing
October 2020

FAM172A promotes follicular thyroid carcinogenesis and may be a marker of FTC.

Endocr Relat Cancer 2020 11;27(11):657-669

Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Our aims were to uncover the role of FAM172A (Family with sequence similarity 172 member A) in the pathogenesis of follicular thyroid carcinoma (FTC) and to evaluate its value in the differential diagnosis between malignant and benign thyroid follicular lesions. FAM172A expression was evaluated by q-PCR, immunoblotting and immunohistochemistry (IHC). The ability of proliferation, migration and invasion of cells were assessed by Cell Counting Kit-8 assay (CCK8), clone-formation and Transwell assays. Nude mouse tumorigenicity assays were used to investigate the role of FAM172A in the pathogenesis of FTC in vivo. The value of FAM172A in the differential diagnosis for FTC was assessed using 120 formalin-fixed paraffin-embedded (FFPE) tissues after the operation and 81 fine-needle aspiration biopsy (FNAB) samples before the operation. FAM172A was highly expressed in FTC tissues and FTC cell lines. Downregulation of FAM172A inhibited the proliferation, invasion and migration of FTC cells through Erk1/2 and JNK pathways. Subcutaneous tumorigenesis in nude mice showed that knockdown of FAM172A inhibited tumor growth and progression in vivo. The FAM172A IHC scores of 3.5 had 92% sensitivity and 63% specificity to separate FTC from benign/borderline thyroid follicular lesions, and 92% sensitivity and 80% specificity to discriminate FTC from benign thyroid follicular lesions in postoperative FFPE samples. The corresponding values were 75 and 78%, and 75 and 89% in preoperative FNA samples, respectively. FAM172A plays an important role in the pathogenesis of FTC through Erk1/2 and JNK pathways. FAM172A may be a potential marker for the preoperative diagnosis of FTC based on the IHC results of thyroid FNAB samples.
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http://dx.doi.org/10.1530/ERC-20-0181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707803PMC
November 2020

INTEDE: interactome of drug-metabolizing enzymes.

Nucleic Acids Res 2021 01;49(D1):D1233-D1243

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
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http://dx.doi.org/10.1093/nar/gkaa755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779056PMC
January 2021

Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma.

Front Oncol 2020 26;10:1545. Epub 2020 Aug 26.

Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.

Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Although studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified. The present study investigated some circulating metabolites associated with overall survival in 276 curatively resected ESCC patients using liquid chromatography/mass spectrometry metabolomics and Kaplan-Meier analysis. Tissue metabolomic analysis of 23-paired ESCC tissue samples was performed to discover metabolic dysregulation in ESCC cancerous tissue. A method consisting of support vector machine recursive feature elimination and LIMMA differential expression analysis was utilized to select promising feature genes within transcriptomic data from 179-paired ESCC tissue samples. Joint pathway analysis with genes and metabolites identified relevant metabolic pathways and targets for ESCC. Four metabolites, kynurenine, 1-myristoyl-glycero-3-phosphocholine (LPC(14:0)sn-1), 2-piperidinone, and hippuric acid, were identified as prognostic factors in the preoperative plasma from ESCC patients. A risk score consisting of kynurenine and LPC(14:0)sn-1 significantly improved the prognostic performance of the tumor-node-metastasis staging system and was able to stratify risk for ESCC. Combined tissue metabolomic analysis and support vector machine recursive feature elimination gene selection revealed dysregulated kynurenine pathway as an important metabolic feature of ESCC, including accumulation of tryptophan, formylkynurenine, and kynurenine, as well as up-regulated indoleamine 2,3-dioxygenase 1 in ESCC cancerous tissue. This work identified for the first time four potential prognostic circulating metabolites. In addition, kynurenine pathway metabolism was shown to be up-regulated tryptophan-kynurenine metabolism in ESCC. Results not only provide a metabolite-based risk score system for prognosis, but also improve the understanding of the molecular basis of ESCC onset and progression, and as well as novel potential therapeutic targets for ESCC.
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http://dx.doi.org/10.3389/fonc.2020.01545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479226PMC
August 2020

LncRNA regulation: New frontiers in epigenetic solutions to drug chemoresistance.

Biochem Pharmacol 2021 07 23;189:114228. Epub 2020 Sep 23.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address:

Long-noncoding RNAs (lncRNAs) have been shown to participate in sensitizing or de-sensitizing cancer cells to chemical drugs during cancer therapeutics. Notably, a plethora of lncRNAs have been confirmed to be associated with epigenetic controllers and regulate histone protein modification or DNA methylation states in the process of gene transcription. This correlation between lncRNAs and epigenetic regulators can induce the expression of core genes to trigger drug resistance. In addition, epigenetic signatures are considered to be effective and attractive biomarkers for monitoring drug therapeutic effects because they are inheritable, dynamic, and reversible. Therefore, the regulatory mechanism between lncRNAs and epigenetic machinery can serve as a novel indicator and target to overcome or reverse drug resistance in cancer therapy. In this review, we also presented a curated selection of computational tools (including online databases and network analysis) in the area of epigenetics. A classic workflow for lncRNA expression network analysis is presented, providing guidance for non-bioinformaticians to identify significant correlation between lncRNAs and other biomolecules.
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http://dx.doi.org/10.1016/j.bcp.2020.114228DOI Listing
July 2021

Progress and trends on the analysis of nucleic acid and its modification.

J Pharm Biomed Anal 2020 Nov 3;191:113589. Epub 2020 Sep 3.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address:

Nucleic acid is a collective term of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and it is an essential substance in all known life forms. As numerous of studies have shown that nucleic acids can be used as therapeutic agents and the abnormality of various nucleic acid and its modification level has been proven to be closely bound up with changes in diseases such as cancer, the development of analytical methods for the nucleic acid and its modification has become one of the research hotspots in the field of life sciences. Compared with classical nucleic acid detection methods such as Northern blotting, Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) and Polymerase Chain Reaction (PCR), novel analytical methods based on nanomaterials, nucleic acid amplification strategies and biosensors can better satisfy the needs for sensitivity and simplicity in current clinical diagnosis. Herein, the progress and trends of analysis of nucleic acid and its modification is discussed, aiming to provide guidance for the detection of nucleic acid and its modification in medical basic research and clinical diagnosis, treatment and prognosis.
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http://dx.doi.org/10.1016/j.jpba.2020.113589DOI Listing
November 2020

Practice of prescription review mode based on data mining in hospital.

Ann Transl Med 2020 Jul;8(14):885

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Background: Our study aims to solve the problems caused by the large numbers of prescriptions and insufficient pharmacists in the hospital by using a prescription review model based on data mining.

Methods: A hospital pharmacy management analysis and decision system was established based on the data of the hospital information system, requirement of pharmacy management and data mining technology. Based on application of this information system, a four-step data mining prescription review model was created and put into practice, which included presentation of model for prescription evaluation, instance problem model, full-scale extraction of problem prescriptions tracking correction and dynamic monitoring of changes in drug dosage distribution for proposing new problem model.

Results: Through the application of this model, the problems caused by overdosage, over-treatment, the combined use of drugs with the same curative effect, and non-indication use of antibacterial drugs in our hospital's prescription reviews were almost solved. The unreasonable rate of prescriptions has remained below 0.05% since 2015, and the unreasonable rate of doctor's orders has been controlled below 0.24%. The proportion of medicines dropped from 45.4% to 28.2%. The proportion of adjuvant drugs used decreased from 21% to 1.6%.

Conclusions: This data mining prescription evaluation model is an efficient prescription quality management tool suitable for implementation in the digital, big data era.
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http://dx.doi.org/10.21037/atm-20-3933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396743PMC
July 2020

Reverse transcription-based loop-mediated isothermal amplification strategy for real-time miRNA detection with phosphorothioated probes.

Anal Chim Acta 2020 Aug 17;1126:1-6. Epub 2020 Jun 17.

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address:

A novel reverse transcription-based loop-mediated isothermal amplification (LAMP) strategy for miRNA detection has been developed. This method consists of two stem-loop probes inspired by the dumbbell-shaped amplicons and inner primers used in conventional LAMP reactions. Termed "terminal hairpin formation and self-priming" (THSP), this reaction incorporates phosphorothioated (PS) modifications to achieve DNA folding and extension without primers. The final signal is monitored by a sequence-specific detection probe, which minimizes the background noise. We suggest that our rapid, facile, and reliable LAMP method will be a promising candidate for detecting miRNA in biomedical applications.
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http://dx.doi.org/10.1016/j.aca.2020.06.007DOI Listing
August 2020

Organic Cation Transporter 1 and 3 Contribute to the High Accumulation of Dehydrocorydaline in the Heart.

Drug Metab Dispos 2020 10 28;48(10):1074-1083. Epub 2020 Jul 28.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

Dehydrocorydaline (DHC), one of the main active components of , is an important remedy for the treatment of coronary heart disease. Our previous study revealed a higher unbound concentration of DHC in the heart than plasma of mice after oral administration of extract or DHC, but the underlying uptake mechanism remains unelucidated. In our investigations, we studied the transport mechanism of DHC in transgenic cells, primary neonatal rat cardiomyocytes, and animal experiments. Using quantitative real-time polymerase chain reaction and Western blotting, we found that uptake transporters expressed in the mouse heart include organic cation transporter 1/3 (OCT1/3) and carnitine/organic cation transporter 1/2 (OCTN1/2). The accumulation experiments in transfected cells showed that DHC was a substrate of OCT1 and OCT3, with of 11.29 ± 3.3 and 8.96 ± 3.7 μM, respectively, but not a substrate of OCTN1/2. Additionally, a higher efflux level (1.71-fold of MDCK-mock) of DHC was observed in MDCK-MDR1 cells than in MDCK-mock cells. Therefore, DHC is a weak substrate for MDR1. Studies using primary neonatal rat cardiomyocytes showed that OCT1/3 inhibitors (quinidine, decynium-22, and levo-tetrahydropalmatine) prevented the accumulation of DHC, whereas OCTN2 inhibitors (mildronate and l-carnitine) did not affect its accumulation. Moreover, the coadministration of OCT1/3 inhibitors (levo-tetrahydropalmatine, THP) decreased the concentration of DHC in the mouse heart. Based on these findings, DHC may be accumulated partly by OCT1/3 transporters and excreted by MDR1 in the heart. THP could alter the distribution of DHC in the mouse heart. SIGNIFICANCE STATEMENT: We reported the cardiac transport mechanism of dehydrocorydaline, highly distributed to the heart after oral administration of o extract or dehydrocorydaline only. Dehydrocorydaline (an OCT1/3 and MDR1 substrate) accumulation in primary cardiomyocytes may be related to the transport activity of OCT1/3. This ability, hampered by selective inhibitors (levo-tetrahydropalmatine, an inhibitor of OCT1/3), causes a nearly 40% reduction in exposure of the heart to dehydrocorydaline. These results suggest that OCT1/3 may contribute to the uptake of dehydrocorydaline in the heart.
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http://dx.doi.org/10.1124/dmd.120.000025DOI Listing
October 2020

Epigenetic Regulation of Differentially Expressed Drug-Metabolizing Enzymes in Cancer.

Drug Metab Dispos 2020 09 29;48(9):759-768. Epub 2020 Jun 29.

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)

Drug metabolism is a biotransformation process of drugs, catalyzed by drug-metabolizing enzymes (DMEs), including phase I DMEs and phase II DMEs. The aberrant expression of DMEs occurs in the different stages of cancer. It can contribute to the development of cancer and lead to individual variations in drug response by affecting the metabolic process of carcinogen and anticancer drugs. Apart from genetic polymorphisms, which we know the most about, current evidence indicates that epigenetic regulation is also central to the expression of DMEs. This review summarizes differentially expressed DMEs in cancer and related epigenetic changes, including DNA methylation, histone modification, and noncoding RNAs. Exploring the epigenetic regulation of differentially expressed DMEs can provide a basis for implementing individualized and rationalized medication. Meanwhile, it can promote the development of new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer. SIGNIFICANCE STATEMENT: This review summarizes the aberrant expression of DMEs in cancer and the related epigenetic regulation of differentially expressed DMEs. Exploring the epigenetic regulatory mechanism of DMEs in cancer can help us to understand the role of DMEs in cancer progression and chemoresistance. Also, it provides a basis for developing new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer.
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http://dx.doi.org/10.1124/dmd.120.000008DOI Listing
September 2020

6-Dithio-2'-deoxyguanosine analogs induce reactive oxygen species-mediated tumor cell apoptosis via bi-targeting thioredoxin 1 and telomerase.

Toxicol Appl Pharmacol 2020 08 1;401:115079. Epub 2020 Jun 1.

Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address:

Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2'-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2'-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis. The vitro antitumor activity of 6-dithio-2'-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2'-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system. Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor, has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug.
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http://dx.doi.org/10.1016/j.taap.2020.115079DOI Listing
August 2020

Extracellular Vesicles in Renal Cell Carcinoma: Multifaceted Roles and Potential Applications Identified by Experimental and Computational Methods.

Front Oncol 2020 7;10:724. Epub 2020 May 7.

College of Pharmaceutical Sciences, Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang University, Hangzhou, China.

Renal cell carcinoma (RCC) is the most common type of kidney cancer. Increasingly evidences indicate that extracellular vesicles (EVs) orchestrate multiple processes in tumorigenesis, metastasis, immune evasion, and drug response of RCC. EVs are lipid membrane-bound vesicles in nanometer size and secreted by almost all cell types into the extracellular milieu. A myriad of bioactive molecules such as RNA, DNA, protein, and lipid are able to be delivered via EVs for the intercellular communication. Hence, the abundant content of EVs is appealing reservoir for biomarker identification through computational analysis and experimental validation. EVs with excellent biocompatibility and biodistribution are natural platforms that can be engineered to offer achievable drug delivery strategies for RCC therapies. Moreover, the multifaceted roles of EVs in RCC progression also provide substantial targets and facilitate EVs-based drug discovery, which will be accelerated by using artificial intelligence approaches. In this review, we summarized the vital roles of EVs in occurrence, metastasis, immune evasion, and drug resistance of RCC. Furthermore, we also recapitulated and prospected the EVs-based potential applications in RCC, including biomarker identification, drug vehicle development as well as drug target discovery.
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http://dx.doi.org/10.3389/fonc.2020.00724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221139PMC
May 2020

L-tetrahydropalmatine attenuates cisplatin-induced nephrotoxicity via selective inhibition of organic cation transporter 2 without impairing its antitumor efficacy.

Biochem Pharmacol 2020 07 8;177:114021. Epub 2020 May 8.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China. Electronic address:

Cisplatin is a first-line chemotherapeutic agent that is widely used for treatment of various solid tumors. However, cisplatin-induced adverse effects, particularly severe nephrotoxicity, preclude its application. In this study, we showed that L-tetrahydropalmatine (L-THP) could selectively inhibit organic cation transporter 2 (OCT2), which plays a crucial role in renal cisplatin uptake from the circulation. Additionally, we demonstrated that L-THP attenuated cisplatin-induced toxicity in mouse primary renal tubular cells. Subsequently, we verified that L-THP reduced the renal accumulation of cisplatin and alleviated cisplatin-induced renal injury in healthy and tumor-bearing nude mice. In healthy mice, co-treatment of L-THP at 5-40 mg/kg reduced cisplatin renal accumulation to 75.0%-49.9% of that in cisplatin alone group (10 mg/kg), and alleviated cisplatin-induced nephrotoxicity. Additionally, it did not alter Pt concentration in the tumor tissue and did not impair its antitumor efficacy in tumor bearing nude mice. The tumor inhibitory rates of cisplatin (10 mg/kg) co-treated with L-THP at 10, 20 and 40 mg/kg were 71.4%, 70.4% and 69.4%, respectively, in H460 tumor bearing nude mice, higher than that of in cisplatin alone group (60.6%), while in HCT116 tumor bearing nude mice, the tumor inhibitory rates in co-treated with 20 mg/kg L-THP was 34.7% (vs 26.3% in cisplatin alone group). Moreover, L-THP reduced cisplatin accumulation and alleviated cisplatin-induced cytotoxicity in human primary renal tubular cells. Therefore, our findings suggested that concomitant administration of L-THP could attenuate cisplatin-induced renal injury via selective inhibition of OCT2 without impairing its antitumor efficacy.
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http://dx.doi.org/10.1016/j.bcp.2020.114021DOI Listing
July 2020
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