scholarly journals A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

2021 ◽  
Vol 22 (22) ◽  
pp. 12502
Author(s):  
Shoji Kokubo ◽  
Shinobu Ohnuma ◽  
Megumi Murakami ◽  
Haruhisa Kikuchi ◽  
Shota Funayama ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Atp Hydrolysis ◽  
Pheophorbide A ◽  
Chemical Library ◽  
Hct 116 ◽  
Potential Inhibitors

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

scholarly journals Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKKγ protein enhances the anticancer effect of chemotherapy

2020 ◽  
Vol 295 (11) ◽  
pp. 3532-3552 ◽  
Author(s):  
Jaganathan Venkatesh ◽  
Sreeja C. Sekhar ◽  
Vino T. Cheriyan ◽  
Magesh Muthu ◽  
Paul Meister ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Inflammatory Cytokines ◽  
High Throughput Screening ◽  
Regulatory Protein ◽  
Chemical Library ◽  
Iκb Kinase ◽  
Pro Inflammatory Cytokines

NF-κB is a pro-inflammatory transcription factor that critically regulates immune responses and other distinct cellular pathways. However, many NF-κB–mediated pathways for cell survival and apoptosis signaling in cancer remain to be elucidated. Cell cycle and apoptosis regulatory protein 1 (CARP-1 or CCAR1) is a perinuclear phosphoprotein that regulates signaling induced by anticancer chemotherapy and growth factors. Although previous studies have reported that CARP-1 is a part of the NF-κB proteome, regulation of NF-κB signaling by CARP-1 and the molecular mechanism(s) involved are unclear. Here, we report that CARP-1 directly binds the NF-κB–activating kinase IκB kinase subunit γ (NEMO or NF-κB essential modulator) and regulates the chemotherapy-activated canonical NF-κB pathway. Importantly, blockade of NEMO–CARP-1 binding diminished NF-κB activation, indicated by reduced phosphorylation of its subunit p65/RelA by the chemotherapeutic agent adriamycin (ADR), but not NF-κB activation induced by tumor necrosis factor α (TNFα), interleukin (IL)-1β, or epidermal growth factor. High-throughput screening of a chemical library yielded a small molecule inhibitor of NEMO–CARP-1 binding, termed selective NF-κB inhibitor 1 (SNI)-1). We noted that SNI-1 enhances chemotherapy-dependent growth inhibition of a variety of cancer cells, including human triple-negative breast cancer (TNBC) and patient-derived TNBC cells in vitro, and attenuates chemotherapy-induced secretion of the pro-inflammatory cytokines TNFα, IL-1β, and IL-8. SNI-1 also enhanced ADR or cisplatin inhibition of murine TNBC tumors in vivo and reduced systemic levels of pro-inflammatory cytokines. We conclude that inhibition of NEMO–CARP-1 binding enhances responses of cancer cells to chemotherapy.

scholarly journals The effect of radiation exposure on multidrug resistance: in vitro and in vivo studies using non-small lung cancer cells

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Shohei Kanno ◽  
Keita Utsunomiya ◽  
Yumiko Kono ◽  
Noboru Tanigawa ◽  
Satoshi Sawada
Keyword(s):  
Lung Cancer ◽  
Multidrug Resistance ◽  
Radiation Exposure ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
In Vivo Studies

Reversal of Multidrug Resistance in Gastric Cancer Cells by E2F-1 Downregulation In Vitro and In Vivo

2013 ◽  
Vol 115 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Lin-Hai Yan ◽  
Xiao-Tong Wang ◽  
Jie Yang ◽  
Fan-Biao Kong ◽  
Chao Lian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Gastric Cancer Cells

Unexpected Growth-Promoting Effect of Oxaliplatin in Excision Repair Cross-Complementation Group 1 Transfected Human Colon Cancer Cells

Pharmacology ◽  
2018 ◽  
Vol 102 (3-4) ◽  
pp. 161-168 ◽  
Author(s):  
Lars Petter Jordheim ◽  
Kamel Chettab ◽  
Emeline Cros-Perrial ◽  
Eva-Laure Matera ◽  
Charles Dumontet
Keyword(s):  
Cancer Cells ◽  
Excision Repair ◽  
Complementation Group ◽  
Human Colon Cancer ◽  
Repair Capacity ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Group 1

The nucleotide excision repair protein excision repair cross-complementation group 1 (ERCC1) has been repeatedly shown to be involved in the sensitivity of cancer cells to platinum derivatives. In order to better understand this process, we transfected HCT-116 cells with a plasmid encoding ERCC1 and studied their in vitro and in vivo behaviour. No main differences were observed for sensitivity to platinum drugs, DNA repair capacity and clonogenicity in vitro. However, ­ERCC1-transfected HCT-116 cells showed paradoxical behaviour in vivo with increased growth in mice treated with oxaliplatin as compared to untreated mice. The Trop2 protein was identified as being potentially involved in the underlying mechanism for these observations, as it was overexpressed in transfected cells. Our results suggest complex regulation of signalling in cancer cells exposed to cancer drugs.

scholarly journals A 3D Heterotypic Multicellular Tumor Spheroid Assay Platform to Discriminate Drug Effects on Stroma versus Cancer Cells

2019 ◽  
Vol 25 (3) ◽  
pp. 265-276
Author(s):  
Zoe Weydert ◽  
Madhu Lal-Nag ◽  
Lesley Mathews-Greiner ◽  
Christoph Thiel ◽  
Henrik Cordes ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
High Throughput Screening ◽  
Drug Testing ◽  
Therapeutic Window ◽  
Multicellular Tumor Spheroid ◽  
Cytotoxic Effects ◽  
Primary Tumors

Three-dimensional (3D) cell culture models are thought to mimic the physiological and pharmacological properties of tissues in vivo more accurately than two-dimensional cultures on plastic dishes. For the development of cancer therapies, 3D spheroid models are being created to reflect the complex histology and physiology of primary tumors with the hopes that drug responses will be more similar to and as predictive as those obtained in vivo. The effect of additional cell types in tumors, such as stromal cells, and the resulting heterotypic cell–cell crosstalk can be investigated in these heterotypic 3D cell cultures. Here, a high-throughput screening-compatible drug testing platform based on 3D multicellular spheroid models is described that enables the parallel assessment of toxicity on stromal cells and efficacy on cancer cells by drug candidates. These heterotypic microtissue tumor models incorporate NIH3T3 fibroblasts as stromal cells that are engineered with a reporter gene encoding secreted NanoLUC luciferase. By tracking the NanoLUC signal in the media over time, a time-related measurement of the cytotoxic effects of drugs on stromal cells over the cancer cells was possible, thus enabling the identification of a therapeutic window. An in vitro therapeutic index parameter is proposed to help distinguish and classify those compounds with broad cytotoxic effects versus those that are more selective at targeting cancer cells.

scholarly journals VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4675
Author(s):  
Silpa Narayanan ◽  
Ying-Fang Fan ◽  
Nehaben A. Gujarati ◽  
Qiu-Xu Teng ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
B Cell Lymphoma ◽  
Mouse Tumor ◽  
Chemotherapeutic Drugs ◽  
Cancer Knowledge ◽  
Colon Cancers

The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.

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