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

Narayanan, Silpa; Gujarati, Nehaben A.; Wang, Jingquan; Wu, Zhuo‐Xun; Koya, Jagadish; Cui, Qingbin; Korlipara, Vijaya L.; Ashby, Charles R.; Chen, Zhe‐Sheng

doi:10.3390/ijms22052463

Cited by 11 publications

(9 citation statements)

References 80 publications

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“…13,34 Inhibition of ABCG2 reverses multidrug resistance in several types of cancers like breast cancer, 35 hepatocellular cancer, 36 lung cancer, 37,38 and colorectal cancer. 39,40 Our results now demonstrate that berbamine reversed the cabazitaxel resistance by inhibition of ABCG2. CXCR4 is another marker often expressed on CSCs, which is related to tumor metastases and recurrence in prostate cancer.…”

Section: Exosomal Mirnas Of Let-7 Family and Mir-26b-5p Induce Apoptosismentioning

confidence: 55%

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p‐STAT3 in prostate cancer

Wang,

Lyu,

Stadlbauer

et al. 2023

The Prostate

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BackgroundCancer stem cells (CSCs) are a small subpopulation of tumor cells with the capability of self‐renewal and drug resistance, leading to tumor progression and disease relapse. Our study aimed to investigate the antitumor effect of berbamine, extracted from berberis amurensis, on prostate CSCs.MethodsSphere formation was used to collect prostate CSCs. The viability, proliferation, invasion, migration, and apoptosis assays were used to evaluate the antitumor effect of berbamine on prostate CSCs. Prostate CSC markers were analyzed by flow cytometry and qRT‐PCR. Small RNA sequencing analysis was conducted to analyse miRNAs. Exosomes were extracted using the ExoQuick‐TC kit and verified by testing exosomal markers using western blot.ResultsBerbamine targets prostate CSCs. Additionally, berbamine enhanced the antitumor effect of cabazitaxel, a second‐line chemotherapeutic drug for advanced prostate cancer, and re‐sensitized Cabazitaxel‐resistant PCa cells (CabaR‐DU145) to cabazitaxel by inhibiting ABCG2, CXCR4, IGF2BP1, and p‐STAT3. Berbamine enhanced the expression of let‐7 miRNA family and miR‐26b and influenced the downstream targets IGF2BP1 and p‐STAT3, respectively. Silencing CXCR4 and ABCG2 downregulated the expression of IGF2BP1 and p‐STAT3, respectively. Importantly, berbamine enhanced also levels of exosomal let‐7 family and miR‐26b, suggesting that berbamine possibly influences the expression of let‐7 family and miR‐26b through exosome delivery. Exosomes derived from berbamine‐treated CabaR‐DU145 cells re‐sensitized the cells to cabazitaxel.ConclusionBerbamine enhanced the toxic activity of cabazitaxel and reversed cabazitaxel resistance potentially through CXCR4/exosomal let‐7/IGF2BP1 and ABCG2/exosomal miR‐26b/p‐STAT3 axes.

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Section: Exosomal Mirnas Of Let-7 Family and Mir-26b-5p Induce Apoptosismentioning

confidence: 55%

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p‐STAT3 in prostate cancer

Wang,

Lyu,

Stadlbauer

et al. 2023

The Prostate

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“…Till now, tremendous efforts have been made to explore the mechanism of MDR, mostly by establishing ABC transporter-overexpressing cancer cell lines (9,29). By comparing parental and resistant cancer cell lines using molecular biology and cellular methods, researchers have identified numerous ABC transporter substrates (21,(30)(31)(32)(33)(34) as well as inhibitors (16,(35)(36)(37)(38)(39)(40). Computational strategies were also developed to boost the modulator discovery process especially multitarget modulators (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…Proper MDR cancer cell models enable researchers to develop potent ABC transporter inhibitors as well as discovery new substrates. For example, recently a number of small molecules have been discovered as strong modulators of major ABC transporters such as ABCB1 (11)(12)(13)(14), ABCG2 (15)(16)(17) and ABCC1 (18).…”

Section: Introductionmentioning

confidence: 99%

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

Wang

Yang

et al. 2021

Front. Oncol.

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Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.

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“…A seeding density of 4×10 3 cells/well was used for the entirety of cell lines. The absorbance was obtained using a spectrophotometer, set at 570 nm as previously described [57][58][59][60]. The concentrations at which around 85% of parental and resistant cells survived (i.e., 1 and 3 µM) were used for the reversal experiments.…”

Section: Mtt Assay For Cytotoxicity Determination and The Reversal Experimentsmentioning

confidence: 99%

The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance

Narayanan

Wang

et al. 2021

Int. J. Biol. Sci.

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Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocytic leukemia. Syk is abundantly present in the cells of hematopoietic lineage that mediates cell proliferation, differentiation, and adhesion. In this current study, we evaluated the efficacy of GS-9973 to overcome multidrug resistance (MDR) due to the overexpression of the ABCG2 transporter in the non-small cell lung cancer (NSCLC) cell line, NCI-H460/MX20. In vitro , 3 μM of GS-9973 reversed the drug resistance of NCI-H460/MX20 cell line to mitoxantrone or doxorubicin. GS-9973, at 3 μM reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein compared to drug-resistant cells incubated with the vehicle. GS-9973 produced a moderate concentration-dependent increase in the ATPase activity of ABCG2 (EC 50 = 0.42 µM) and molecular docking data indicated that GS-9973 had a high affinity (-10.226 kcal/mol) for the substrate-binding site of ABCG2. Finally, HPLC analysis proved that the intracellular concentration of GS-9973 is not significantly different in both parental and resistant cell lines. In conclusion, our study suggests that in vitro , GS-9973 in combination with certain anticancer drugs, represent a strategy to overcome ABCG2-mediated MDR cancers.

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

Cited by 11 publications

References 80 publications

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p‐STAT3 in prostate cancer

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p‐STAT3 in prostate cancer

Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression

The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance

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