Publications by authors named "Zhe-Sheng Chen"

266 Publications

CMP25, a synthetic new agent, targets multidrug resistance-associated protein 7 (MRP7/ABCC10).

Biochem Pharmacol 2021 Jun 11;190:114652. Epub 2021 Jun 11.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address:

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.
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http://dx.doi.org/10.1016/j.bcp.2021.114652DOI Listing
June 2021

CUL4 lung adenocarcinomas are dependent on the CUL4-p21 ubiquitin signaling for proliferation and survival.

Am J Pathol 2021 Jun 10. Epub 2021 Jun 10.

Department of Pathology and Laboratory Medicine, The Joan and Stanford I. Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address:

Cullin 4A and 4B ubiquitin ligases are often highly accumulated in human malignancies, and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. In this study, we report that both CUL4A and CUL4B are highly expressed in non-small cell lung cancer (NSCLC) patients, and high expression of both is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4A) or CUL4B (CUL4B) leads to cell cycle arrest at G1 and loss of proliferation and viability of NSCLC cells both in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLC. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells upon CUL4 silencing. Knockdown of p21 rescued the G1 arrest of CUL4A or CUL4B NSCLC cells and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4A CUL4B may serve as a prognostic marker and therapeutic target for NSCLC patients.
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http://dx.doi.org/10.1016/j.ajpath.2021.05.018DOI Listing
June 2021

Features of Cytokine Storm Identified by Distinguishing Clinical Manifestations in COVID-19.

Front Public Health 2021 24;9:671788. Epub 2021 May 24.

College of Pharmacy and Health Science, St. John's University, New York, NY, United States.

Coronavirus disease 2019 (COVID-19) is caused by a new coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently spreading all over the world. In this paper, we developed a practical model for identifying the features of cytokine storm, which is common in acute infectious diseases and harmful manifestation of COVID-19, by distinguishing major and minor clinical events. This model is particularly suitable for identifying febrile and infectious diseases like COVID-19. Based on this model, features of cytokine storm and pathogenesis of COVID-19 have been proposed to be a consequence of the disequilibrated cytokine network resulting from increased biological activity of transforming growth factor-β (TGF-β), which induces certain clinical manifestations such as fatigue, fever, dry cough, pneumonia, abatement and losing of olfactory, and taste senses in some patients. Research and clarification of the pathogenesis of COVID-19 will contribute to precision treatment. Various anti-TGF-β therapies may be explored as potential COVID-19 treatment. This novel model will be helpful in reducing the widespread mortality of COVID-19.
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http://dx.doi.org/10.3389/fpubh.2021.671788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180556PMC
June 2021

AZ32 Reverses ABCG2-Mediated Multidrug Resistance in Colorectal Cancer.

Front Oncol 2021 20;11:680663. Epub 2021 May 20.

Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.

Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.
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http://dx.doi.org/10.3389/fonc.2021.680663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173085PMC
May 2021

A Circulating Exosome RNA Signature Is a Potential Diagnostic Marker for Pancreatic Cancer, a Systematic Study.

Cancers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, New Haven, CT 06520, USA.

Several exosome proteins, miRNAs and mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in the diagnosis of pancreatic cancer. The purpose of this study was to investigate the potential of circulating exosome RNAs in pancreatic cancer detection. By retrieving RNA-seq data from publicly accessed databases, differential expression and random-effects meta-analyses were performed. The results showed that pancreatic cancer had a distinct circulating exosome RNA signature in healthy individuals, and that the top 10 candidate exosome RNAs could distinguish patients from healthy individuals with an area under the curve (AUC) of 1.0. Three (, and ) of the 10 genes in exosomes had similar differential patterns to those in tumor tissues based on RNA-seq data. In the validation dataset, the levels of these three genes in exosomes displayed good performance in distinguishing cancer from both chronic pancreatitis (AUC = 0.815) and healthy controls (AUC = 0.8558), whereas a slight difference existed between chronic pancreatitis and healthy controls (AUC = 0.586). Of the three genes, the level of was positively associated with status. However, there was no significant difference in the levels of the three genes across the disease stages (stages I-IV). These findings indicate that circulating exosome RNAs have a potential early detection value in pancreatic cancer, and that a distinct exosome RNA signature exists in distinguishing pancreatic cancer from healthy individuals.
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http://dx.doi.org/10.3390/cancers13112565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197236PMC
May 2021

Recent progress on targeting leukemia stem cells.

Drug Discov Today 2021 May 23. Epub 2021 May 23.

School of Pharmacy, Weifang Medical University, Weifang 261053, PR China. Electronic address:

Leukemia is a type of malignant clonal disease of hematopoietic stem cells (HSCs). A small population of leukemic stem cells (LSCs) are responsible for the initiation, drug resistance, and relapse of leukemia. LSCs have the ability to form tumors after xenotransplantation in immunodeficient mice and appear to be common in most human leukemias. Therefore, the eradication of LSCs is an approach with the potential to improve survival or even to cure leukemia. Using recent research in the field of LSCs, we summarize the targeted therapy approaches for the removal of LSCs through surface markers including immune checkpoint molecules, pathways influencing LSC survival, or the survival microenvironment of LSCs. In addition, we introduce the survival microenvironment and survival regulation of LSCs.
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http://dx.doi.org/10.1016/j.drudis.2021.05.009DOI Listing
May 2021

Mechanisms of thrombosis and research progress on targeted antithrombotic drugs.

Drug Discov Today 2021 Apr 22. Epub 2021 Apr 22.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, NY 11439, USA. Electronic address:

Globally, the incidence of thromboembolic diseases has increased in recent years, accompanied by an increase in patient mortality. Currently, several targeting delivery strategies have been developed to treat thromboembolic diseases. In this review, we discuss the mechanisms of thrombolysis and current anticoagulant drugs, particularly those with targeting capability, highlighting advances in the accurate treatment of thrombolysis with fewer adverse effects. Such approaches include magnetic drug-loading systems combined with molecular imaging to recanalize blood vessels and systems based on chimeric Arg-Gly-Asp (RGD) sequences that can target platelet glycoprotein receptor. With such progress in targeted antithrombotic drugs, targeted thrombolysis treatment shows significant potential benefit for patients.
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http://dx.doi.org/10.1016/j.drudis.2021.04.023DOI Listing
April 2021

Cabozantinib Reverses Topotecan Resistance in Human Non-Small Cell Lung Cancer NCI-H460/TPT10 Cell Line and Tumor Xenograft Model.

Front Cell Dev Biol 2021 22;9:640957. Epub 2021 Mar 22.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Cabozantinib (CBZ) is a small molecule tyrosine kinase receptor inhibitor, which could also inhibit the ABCG2 transporter function. Therefore, CBZ could re-sensitize cancer cells that are resistant to ABCG2 substrate drugs including topotecan (TPT). However, its reversal effect against TPT resistance has not been tested in a TPT-induced resistant cancer model. In this study, a new TPT selected human non-small cell lung cancer (NSCLC)-resistant cell model NCI-H460/TPT10 with ABCG2 overexpression and its parental NCI-H460 cells were utilized to investigate the role of CBZ in drug resistance. The study showed that CBZ, at a non-toxic concentration, could re-sensitize NCI-H460/TPT10 cells to TPT by restoring intracellular TPT accumulation via inhibiting ABCG2 function. In addition, the increased cytotoxicity by co-administration of CBZ and TPT may be contributed by the synergistic effect on downregulating ABCG2 expression in NCI-H460/TPT10 cells. To further verify the applicability of the NCI-H460/TPT10 cell line to test multidrug resistance (MDR) reversal agents and to evaluate the efficacy of CBZ on reversing TPT resistance, a tumor xenograft mouse model was established by implanting NCI-H460 and NCI-H460/TPT10 into nude mice. The NCI-H460/TPT10 xenograft tumors treated with the combination of TPT and CBZ dramatically reduced in size compared to tumors treated with TPT or CBZ alone. The TPT-resistant phenotype of NCI-H460/TPT10 cell line and the reversal capability of CBZ in NCI-H460/TPT10 cells could be extended from cell model to xenograft model. Collectively, CBZ is considered to be a potential approach in overcoming ABCG2-mediated MDR in NSCLC. The established NCI-H460/TPT10 xenograft model could be a sound clinically relevant resource for future drug screening to eradicate ABCG2-mediated MDR in NSCLC.
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http://dx.doi.org/10.3389/fcell.2021.640957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019832PMC
March 2021

Long noncoding RNAs have pivotal roles in chemoresistance of acute myeloid leukemia.

Drug Discov Today 2021 Mar 27. Epub 2021 Mar 27.

Department of Pharmaceutical Sciences, St John's University, New York, NY, USA. Electronic address:

Many patients with acute myeloid leukemia (AML) experience poor outcomes following traditional high-dose chemotherapies and complete remission rates remain suboptimal. Chemoresistance is an obstacle to effective chemotherapy and the precise mechanisms involved remain to be determined. Recently, long noncoding RNAs (lncRNAs) have been identified as relevant factors in the development of drug resistance in patients with AML. Furthermore, accumulating data support the importance of lncRNAs as potentially useful novel therapeutic targets in many cancers. Here, we review the role of lncRNAs in the development and induction of the chemoresistance in AML, and suggest lncRNAs as novel molecular markers for diagnosis, prediction of patient response to chemotherapy, and novel therapeutic targets for AML.
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http://dx.doi.org/10.1016/j.drudis.2021.03.017DOI Listing
March 2021

OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways.

Front Cell Dev Biol 2021 4;9:652972. Epub 2021 Mar 4.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.

Acute myelogenous leukemia (AML) is characterized by blockage of cell differentiation leading to the accumulation of immature cells, which is the most prevalent form of acute leukemia in adults. It is well known that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the preferred drugs for acute promyelocytic leukemia (APL). However, they can lead to irreversible resistance which may be responsible for clinical failure after complete remission (CR). Moreover, the differentiation therapy of ATRA-based treatment has not been effective against AML with t(8;21) translocation. Here we aimed to identify the differentiation effect of OGP46 on AML cell lines (HL-60, NB4, and Kasumi-1) and explore its possible mechanisms. We found that OGP46 has significant inhibitory activity against these cells by triggering cell differentiation with cell-cycle exit at G1/G0 and inhibited the colony-formation capacity of the AML cells. It was shown that OGP46 induced the differentiation of NB4 cells via the transcriptional misregulation in cancer signaling pathway by PML-RARα depletion, while it was attributed to the hematopoietic cell lineage and phagosome pathway in Kasumi-1 cells, which are all critical pathways in cell differentiation. These results highlight that OGP46 is an active agent not only in the APL cell line NB4 but also in AML-M2 cell lines, especially Kasumi-1 with t(8;21) translocation. Therefore, OGP46 may be a potential compound for surmounting the differentiation blockage in AML.
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http://dx.doi.org/10.3389/fcell.2021.652972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969801PMC
March 2021

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach.

Front Cell Dev Biol 2021 4;9:649434. Epub 2021 Mar 4.

College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Chronic myelogenous leukemia (CML) typically results from a reciprocal translocation between chromosomes 9 and 22 to produce the oncogene that when translated, yields the p210 BCR-ABL protein in more than 90% of all CML patients. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation. Although the use of the BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib have increased the overall survival of CML patients, their use is limited by drug resistance and severe adverse effects. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. Therefore, in this study, we sought to find novel compounds using Hypogen and Hiphip pharmacophore models based on the structures of clinically approved BCR-ABL TKIs. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. The hit compounds were further screened using Lipinski's rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. Our results indicated that compound ZINC21710815 significantly inhibited the proliferation of K562, BaF3/WT, and BaF3/T315I leukemia cells by inducing cell cycle arrest. The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo evaluation.
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http://dx.doi.org/10.3389/fcell.2021.649434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969810PMC
March 2021

Overexpression of ABCC1 Confers Drug Resistance to Betulin.

Front Oncol 2021 25;11:640656. Epub 2021 Feb 25.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.

Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.
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http://dx.doi.org/10.3389/fonc.2021.640656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951056PMC
February 2021

Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line.

Front Oncol 2020 22;10:624954. Epub 2021 Feb 22.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, United States.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance and improve CRC treatment .
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http://dx.doi.org/10.3389/fonc.2020.624954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937870PMC
February 2021

Therapeutic strategies to overcome taxane resistance in cancer.

Drug Resist Updat 2021 Mar 27;55:100754. Epub 2021 Feb 27.

Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India. Electronic address:

One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and β-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.
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http://dx.doi.org/10.1016/j.drup.2021.100754DOI Listing
March 2021

Metal (II) Complexes of Fluconazole: Thermal, XRD and Cytotoxicity Studies.

Iran J Pharm Res 2020 ;19(3):171-182

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

We report thermal, X-ray diffraction (XRD) and cytotoxicity studies of complexes of fluconazole (FCZ) with Cu (II), Fe(II), Cd(II), Co(II), Ni(II), and Mn(II). From XRD measurements, FCZ and its metal complexes were identified as polycrystalline. Marked differences in the X-ray patterns of drug and its metal complexes revealed that the complexes are indeed different compounds and not just the mixture of the starting materials. Unlike pristine FCZ, which did not exhibit cytotoxicity, three complexes derived from Fe(II), Cu(II) and Co (II) proved to be effective in the cytotoxicity assay. The Cu(II)-FCZ exhibited significant activity against SNB-19, HCT-15, COLO-205, and KB-3-1 cell lines, while Fe(II)-FCZ and Co(II)-FCZ were found cytotoxic only to KB-3-1 cell line. For the pure FCZ, thermogravimetry revealed massive weight loss in the temperature range of 215 to 297 °C, due to the volatilization of FCZ. All the complexes followed multi-stage degradation profiles, eventually resulting in the formation of metal oxides. For pure FCZ, differential scanning calorimetry revealed melting point at 137 °C, followed by two further endothermic transitions at 294 °C and 498.44 °C representing the volatilization and subsequent degradation of FCZ, respectively. The absence of endothermic FCZ melting peak at around 137 °C indicates that the complexes represent different compounds. All complexes exhibit endothermic transitions at around 240-300 °C, representing melting and removal of ligand moiety, followed by another endothermic transition at around 498-499 °C, representing the ligand decomposition.
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http://dx.doi.org/10.22037/ijpr.2020.1101142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757997PMC
January 2020

Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities.

Eur J Med Chem 2021 Apr 24;216:113316. Epub 2021 Feb 24.

State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address:

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2021.113316DOI Listing
April 2021

The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this study, we determined the efficacy of the novel benzamide derivative, VKNG-2, to overcome MDR due to the overexpression of the ABCG2 transporter in the colon cancer cell line, S1-M1-80. , 5 μM of VKNG-2 reversed the resistance of S1-M1-80 cell line to mitoxantrone (70-fold increase in efficacy) or SN-38 (112-fold increase in efficacy). In contrast, 5 μM of VKNG-2 did not significantly alter either the expression of ABCG2, AKT, and PI3K p110β protein or the subcellular localization of the ABCG2 protein compared to colon cancer cells incubated with the vehicle. Molecular docking data indicated that VKNG-2 had a high docking score (-10.2 kcal/mol) for the ABCG2 transporter substrate-drug binding site whereas it had a low affinity on ABCB1 and ABCC1 transporters. Finally, VKNG-2 produced a significant concentration-dependent increase in ATPase activity (EC = 2.3 µM). In conclusion, our study suggests that , VKNG-2 reverses the resistance of S1-M1-80, a cancer cell line resistant to mitoxantrone and SN-38, by inhibiting the efflux function of the ABCG2 transporter.
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http://dx.doi.org/10.3390/ijms22052463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957563PMC
February 2021

OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance.

Front Pharmacol 2021 15;12:620874. Epub 2021 Feb 15.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.
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http://dx.doi.org/10.3389/fphar.2021.620874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917255PMC
February 2021

Natural Product as Substrates of ABC Transporters: A Review.

Recent Pat Anticancer Drug Discov 2021 Feb 18. Epub 2021 Feb 18.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, . United States.

Background: To date, many compounds extracting from natural products have anti-tumor activity, such as citronellol, ellagitannin-containing pomegranate extract, etc. Evidence from clinical context shows that multidrug resistance is an obstacle that impedes the effectiveness of natural products, such as chemotherapeutic agents paclitaxel and vincristine. Overexpression of ATP-Binding Cassette (ABC) transporters is the leading cause of MDR. Therefore, it is crucial to investigate whether these natural products are substrates of MDR-associated ABC transporters, which may benefit the development of their clinical usage.

Objective: This review summarizes the latest insight on natural products possessing substrate profile and analyzed some possible regularity to provide direction for future drug discovery.

Conclusion: The anti-tumor effects of natural products are constantly being explored, but the drug resistance issues cannot be ignored, which limits their prospects as anti-tumor drugs to a certain extent. At the same time, some natural products are taken as a daily diet, and their possible role in increasing the drug resistance of the substrate should arouse the attention of clinical cancer patients.
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http://dx.doi.org/10.2174/1574892816666210218220943DOI Listing
February 2021

Target Inhibition of CBP Induced Cell Senescence in BCR-ABL- T315I Mutant Chronic Myeloid Leukemia.

Front Oncol 2020 8;10:588641. Epub 2021 Jan 8.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

The treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, has yielded clinical success. However, the direct targeting of BCR-ABL does not eradicate CML cells expressing mutant BCR-ABL, especially the T315I mutation in BCR-ABL. Moreover, increasing mutations were identified in BCR-ABL domain, resulting in TKIs resistance recently. It is necessary to find BCR-ABL-independent target for treating CML patients with various mutations, including T315I mutation in BCR-ABL. The dichotomous behavior of CREB binding protein (CBP) and E1A protein (p300), recruited by β-catenin associated with self-renewal and differentiation, have been identified in hematopoietic stem cells, respectively. In this study, CBP was aberrantly expressed in CML cells on the basis of Oncomine dataset. The β-catenin bound with much more CBP than p300 in CML cells. Down-regulation of CBP inhibited cell proliferation capacity and increased the binding of β-catenin to p300, thus promoting cell differentiation and p53-dependent cell senescence in CML cells with either wild type or T315I mutant BCR-ABL and models. These demonstrate CBP blockage can be developed for the treatment of CML independent of BCR-ABL mutation status including T315I.
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http://dx.doi.org/10.3389/fonc.2020.588641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873979PMC
January 2021

Construction and Validation of a Nomogram for Predicting Progression- Free Survival in Patients with Early-Stage Testicular Germ Cell Tumor.

Recent Pat Anticancer Drug Discov 2021 ;16(1):44-53

Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China

Background: Testicular Germ Cell Tumor (TGCT) is the most common malignant tumor in young men, but there is a lack of a prediction model to evaluate the prognosis of patients with TGCT.

Objective: To explore the prognostic factors for Progression-Free Survival (PFS) and construct a nomogram model for patients with early-stage TGCT after radical orchiectomy.

Methods: Patients with TGCT from The Cancer Genome Atlas (TCGA) database were used as the training cohort; univariate and multivariate cox analysis was performed. A nomogram was constructed based on the independent prognostic factors. Patients from the Nanfang Hospital affiliated with Southern Medical University were used as the cohort to validate the predictive ability using the nomogram model. Harrell's concordance index (C-index) and calibration plots were used to evaluate the nomogram.

Results: A total of 110 and 62 patients with TGCT were included in the training cohort and validation cohort, respectively. Lymphatic Vascular Invasion (LVI), American Joint Committee on Cancer (AJCC) stage and adjuvant therapy were independent prognostic factors in multivariate regression analyses and were included to establish a nomogram. The C-index in the training cohort for 1- , 3-, and 5-year PFS were 0.768, 0.74, and 0.689, respectively. While the C-index for 1-, 3-, and 5- year PFS in the external validation cohort were 0.853, 0.663 and 0.609, respectively. The calibration plots for 1-, 3-, and 5-year PFS in the training and validation cohort showed satisfactory consistency between predicted and actual outcomes. The nomogram revealed a better predictive ability for PFS than AJCC staging system.

Conclusion: The nomogram as a simple and visual tool to predict individual PFS in patients with TGCT could guide clinicians and clinical pharmacists in therapeutic strategy.
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http://dx.doi.org/10.2174/1574892816666210211092108DOI Listing
January 2021

The role of androgen therapy in prostate cancer: from testosterone replacement therapy to bipolar androgen therapy.

Drug Discov Today 2021 May 6;26(5):1293-1301. Epub 2021 Feb 6.

Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China; Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address:

Testosterone replacement therapy (TRT) is the primary treatment for male testosterone deficiency. This therapy raises concerns over the risk of prostate cancer (PC), because testosterone has historically been considered the fuel for PC. We discuss the re-evaluation of the relationship between androgen and PC, and highlight the safety of TRT in the treatment of symptomatic men with testosterone deficiency who have low-risk disease after treatment for localized PC with surgery or radiation. Furthermore, we review the clinical application and potential mechanisms of bipolar androgen therapy (BAT) in the treatment of castration-resistant PC, emphasizing that much remains to be done before BAT can be broadly applied.
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http://dx.doi.org/10.1016/j.drudis.2021.01.034DOI Listing
May 2021

Gold nanoparticles: synthesis, physiochemical properties and therapeutic applications in cancer.

Drug Discov Today 2021 May 4;26(5):1284-1292. Epub 2021 Feb 4.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY 11439, USA. Electronic address:

Gold nanoparticles (AuNPs) have been shown to be useful as carriers of various anticancer drugs as well as diagnosis platforms. In this review, we discuss the synthesis and physiochemical properties of AuNPs. We also highlight the photothermal and photodynamic properties of AuNPs and relevant applications in therapeutic studies. Furthermore, we review the applications of AuNPs in cancer treatment as and their underlying anticancer mechanisms in multiple types of cancer.
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http://dx.doi.org/10.1016/j.drudis.2021.01.030DOI Listing
May 2021

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells.

Front Pharmacol 2020 14;11:615824. Epub 2021 Jan 14.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.
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http://dx.doi.org/10.3389/fphar.2020.615824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841342PMC
January 2021

Multidrug resistance proteins (MRPs): Structure, function and the overcoming of cancer multidrug resistance.

Drug Resist Updat 2021 Jan 13;54:100743. Epub 2021 Jan 13.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address:

ATP-binding cassette (ABC) transporters mediate the ATP-driven translocation of structurally and mechanistically distinct substrates against steep concentration gradients. Among the seven human ABC subfamilies namely ABCA-ABCG, ABCC is the largest subfamily with 13 members. In this respect, 9 of the ABCC members are termed "multidrug resistance proteins" (MRPs1-9) due to their ability to mediate cancer multidrug resistance (MDR) by extruding various chemotherapeutic agents or their metabolites from tumor cells. Furthermore, MRPs are also responsible for the ATP-driven efflux of physiologically important organic anions such as leukotriene C, folic acid, bile acids and cAMP. Thus, MRPs are involved in important regulatory pathways. Blocking the anticancer drug efflux function of MRPs has shown promising results in overcoming cancer MDR. As a result, many novel MRP modulators have been developed in the past decade. In the current review, we summarize the structure, tissue distribution, biological and pharmacological functions as well as clinical insights of MRPs. Furthermore, recent updates in MRP modulators and their therapeutic applications in clinical trials are also discussed.
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http://dx.doi.org/10.1016/j.drup.2021.100743DOI Listing
January 2021

Overexpression of human ATP-binding cassette transporter ABCG2 contributes to reducing the cytotoxicity of GSK1070916 in cancer cells.

Biomed Pharmacother 2021 Apr 12;136:111223. Epub 2021 Jan 12.

Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, PR China. Electronic address:

The emergence of multidrug resistance (MDR) is one of the main factors that impair therapeutic outcome in cancer therapy. Among all the factors that contribute to MDR, overexpression of ABCG2 transporter has been described as a key factor. GSK1070916 is a potent Aurora kinase inhibitor with broad anticancer effects. The robust efficacy shown in preclinical studies allowed the drug progress to clinical investigation. However, the potential mechanisms of acquired resistance to GSK1070916 remain inconclusive. Since several Aurora kinase inhibitors were reported to be transported substrates of ABCG2, we aimed to identify the potential interaction of GSK1070916 with ABCG2. Our data showed that ABCG2-overexpressing cells demonstrated high resistance-fold to GSK1070916 compared to the parental cells. In addition, combination of GSK1070916 with an ABCG2 inhibitor was able to restore its sensitivity. The multicellular tumor spheroid assay supported this finding by demonstrating attenuated growth inhibition in ABCG2-overexpressing tumor spheroids. In addition, the ABCG2 ATPase assay and computational modeling suggested that GSK1070916 could bind to ABCG2 substrate-binding site. The HPLC assay provided another direct evidence that ABCG2-overexpressing cells showed attenuated intracellular accumulation of GSK1070916, and such phenomenon was abolished by Ko143, a known ABCG2 inhibitor. Furthermore, GSK1070916 was able to hinder the efflux activity of ABCG2, indicating possible drug-drug interactions with other ABCG2 substrate drugs. In summary, we revealed that overexpression of ABCG2 can cause GSK1070916 resistance in cancer cells. The combination of an ABCG2 inhibitor with GSK1070916 may be a rational strategy to overcome the drug resistance and should be considered for clinical investigation.
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http://dx.doi.org/10.1016/j.biopha.2021.111223DOI Listing
April 2021

Multifaceted anti-colorectal tumor effect of digoxin on HCT8 and SW620 cells .

Gastroenterol Rep (Oxf) 2020 Dec 10;8(6):465-475. Epub 2020 Dec 10.

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin, P. R. China.

Background: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Novel drugs for CRC therapy are urgently needed. Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years. Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC. Here, we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism.

Methods: Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and plate colony formation assay. The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry. The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay. Anti-angiogenic effect was examined by determining the inhibition against proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Mechanism study was performed by Western blot, enzyme-linked immunosorbent assay (ELISA), and gelatin-zymography assay.

Results: Digoxin potently inhibited cell proliferation, induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells, respectively. No obvious apoptosis was observed in the treated cells. Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion. Meanwhile, the expression of MMP2, MMP9, and phosphorylated Integrinβ1 were decreased. Digoxin inhibited the proliferation, migration, and tube formation of HUVECs and reduced HIF1α expression and vascular endothelial growth factor A (VEGF-A) secretion in HCT8 cells, suggesting anti-angiogenic activity. Furthermore, digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells.

Conclusion: Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.
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http://dx.doi.org/10.1093/gastro/goaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793120PMC
December 2020

Establishment and Characterization of a Topotecan Resistant Non-small Cell Lung Cancer NCI-H460/TPT10 Cell Line.

Front Cell Dev Biol 2020 23;8:607275. Epub 2020 Dec 23.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

While topotecan (TPT) is a first- and second-line chemotherapeutic drug in treating lung cancer, the development of drug resistance in tumors still reserves as a major obstacle to chemotherapeutic success. Therefore, a better understanding of the mechanisms of topotecan resistance is critical. In this study, the first topotecan-resistant human non-small cell lung cancer (NSCLC) cell line, termed NCI-H460/TPT10, was established from the parental NCI-H460 cell line. NCI-H460/TPT10 cells exhibited a 394.7-fold resistance to TPT, and cross-resistance to SN-38, mitoxantrone, and doxorubicin, compared to parental NCI-H460 cells. Overexpression of ABCG2 localized on the cell membrane, but not ABCB1 or ABCC1, was found in NCI-H460/TPT10 cells, indicating that ABCG2 was likely to be involved in topotecan-resistance. This was confirmed by the abolishment of drug resistance in NCI-H460/TPT10 cells after knockout. Moreover, the involvement of functional ABCG2 as a drug efflux pump conferring multidrug resistance (MDR) was indicated by low intracellular accumulation of TPT in NCI-H460/TPT10 cells, and the reversal effects by ABCG2 inhibitor Ko143. The NCI-H460/TPT10 cell line and its parental cell line can be useful for drug screening and developing targeted strategies to overcome ABCG2-mediated MDR in NSCLC.
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http://dx.doi.org/10.3389/fcell.2020.607275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786180PMC
December 2020

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor.

Front Cell Dev Biol 2020 8;8:601400. Epub 2020 Dec 8.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR . Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.
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http://dx.doi.org/10.3389/fcell.2020.601400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753047PMC
December 2020

Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5-]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators.

J Med Chem 2020 12 5;63(24):15979-15996. Epub 2020 Dec 5.

School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-]pyrimidines as new ABCB1 modulators, of which significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC = 22.02 nM). Mechanistic studies indicated that significantly increased the intracellular concentration of PTX and [H]-PTX while decreasing the efflux of [H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that could stabilize ABCB1 by directly binding to ABCB1. could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, increased the sensitivity of SW620/Ad300 cells to PTX without observed toxicity. Collectively, is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01741DOI Listing
December 2020