Multidrug Resistance Reversal Agent, NSC77037, Identified with a Cell-Based Screening Assay

2010 ◽  
Vol 15 (3) ◽  
pp. 287-296 ◽  
Author(s):  
Michiro Susa ◽  
Edwin Choy ◽  
Cao Yang ◽  
Joseph Schwab ◽  
Henry Mankin ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Small Molecule ◽  
Cancer Resistance ◽  
Screening Assay ◽  
A Cell ◽  
Resistance Protein ◽  
Mdr Reversal

The development of multidrug resistance (MDR) remains a significant obstacle in treating cancer patients with chemotherapy. To identify small-molecule compounds that can reverse MDR, the authors used a cell-based screening assay with an MDR ovarian cancer cell line. Incubating MDR cells with a sublethal concentration of paclitaxel in combination with each of 2000 small-molecule compounds from the National Cancer Institute Diversity Set Library, they identified NSC77037. The cytotoxic activity of NSC77037 and the duration of its effect were evaluated in vitro using a panel of cancer cell lines expressing permeability glycoprotein (Pgp), multiple drug resistance protein 1 (MRP 1), and breast cancer resistance protein (BCRP). The mechanism of its effects was further analyzed by assessing the retention of calcein and Pgp-ATPase activity. The relative potency of MDR reversal by NSC77037 was significantly higher than that of frequently used MDR reversal agents such as verapamil and cyclosporine A. NSC77037 reversed Pgp without reversing MRP or BCRP-mediated MDR. NSC77037, at a concentration of >10 µM, moderately inhibited the proliferation of both sensitive and resistant cell lines, but the inhibitory effect of NSC77037 was not altered by coincubation with the Pgp inhibitor verapamil, suggesting that NSC77037 itself is not a substrate of Pgp. NSC77037 directly inhibited the function of Pgp in a dose-dependent manner, but it did not alter the protein expression level of Pgp. The use of NSC77037 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.

Inhibitors of cancer cell multidrug resistance mediated by breast cancer resistance protein (BCRP/ABCG2)

2006 ◽  
Vol 17 (3) ◽  
pp. 239-243 ◽  
Author(s):  
Abdelhakim Ahmed-Belkacem ◽  
Alexandre Pozza ◽  
Sira Macalou ◽  
Jose?? M. Pe??rez-Victoria ◽  
Ahce`ne Boumendjel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Cancer Cell ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Resistance Protein

Acute Myeloid Leukemia Cells Are Resistant to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) by a Mechanism Independent of Multidrug Resistance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4385-4385
Author(s):  
Stacy M. Fricke ◽  
Hans Minderman ◽  
Kieran L. O’Loughlin ◽  
Jinrong Cheng ◽  
Elizabeth A. Repasky ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Receptor Expression ◽  
Cancer Resistance ◽  
Abc Proteins ◽  
Trail Receptors ◽  
Resistance Protein ◽  
Acute Myeloid

Abstract Multidrug resistance (MDR) associated with overexpression of the ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP) is an obstacle to the successful treatment of AML. Apo2L/TRAIL binds to the extracellular death receptors DR4 and DR5 and induces tumor-specific apoptosis in diverse malignancies. Given that Apo2L/TRAIL induces apoptosis via signal transduction pathways, it has the potential to be effective in cells with MDR mediated by ABC proteins. Cell lines with MDR mediated by ABC proteins and acute myeloid leukemia (AML) cells from 10 patients (6 untreated, 4 relapsed/refractory) were tested for expression of the Apo2L/TRAIL receptors DR4 and DR5 and decoy receptors DcR1 and DcR2 by flow cytometry and for cytotoxic and pro-apoptotic effects of Apo2L/TRAIL (Genentech, Inc.). Parental HL60 and 8226 cells and resistant HL60/VCR (Pgp) and HL60/Adr (MRP-1) cells demonstrated expression of DR4 and DR5 and lack of expression of DcR1 and DcR2, while 8226/MR20 (BCRP) had only low-level expression of DR5. Parental HL60 and 8226 cells displayed dose-dependent cytotoxicity in response to Apo2L/TRAIL. HL60/VCR and HL60/Adr were 3- and 5-fold more resistant to Apo2L/TRAIL than parental HL60 cells, but were not sensitized by the Pgp- and MRP-1-specific modulators PSC-833 and MK571, demonstrating that resistance was not mediated by Pgp and MRP-1. 8226/MR20 (BCRP) cells were not resistant to Apo2L/TRAIL in relation to parental 8226 cells. Of note, cyclosporine A (CsA) sensitized all parental and multidrug resistant cells to Apo2L/TRAIL, lowering IC50’s 2- to 5-fold, likely by a pro-apoptotic mechanism independent of MDR modulation. AML blasts did not express Apo2L/TRAIL receptors, with the exception of DR5 in two samples, both DR5 and DcR1 in one and DcR1 alone in a fourth. Moreover, AML blasts showed minimal or no apoptosis following 24- and 48-hour in vitro exposure to Apo2L/TRAIL in concentrations up to 1 ug/ml, 30-fold higher than the highest cytotoxic concentration in cell lines, and no enhancement of apoptosis by CsA. In conclusion, MDR mediated by ABC proteins does not appear to be associated with Apo2L/TRAIL resistance in cell line models, but AML cells are resistant to Apo2L/TRAIL, and this resistance is associated at least in part with lack of receptor expression. Strategies for upregulating Apo2L/TRAIL receptor expression on AML cells warrant further study.

scholarly journals Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

2021 ◽  
Vol 22 (8) ◽  
pp. 4153
Author(s):  
Kutlwano R. Xulu ◽  
Tanya N. Augustine
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Antiplatelet Therapy ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

scholarly journals MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients

2021 ◽  
Vol 22 (10) ◽  
pp. 5382
Author(s):  
Pei-Yi Chu ◽  
Hsing-Ju Wu ◽  
Shin-Mae Wang ◽  
Po-Ming Chen ◽  
Feng-Yao Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
Protein Expression ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Expression Ratio

(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer.

scholarly journals Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells

2021 ◽  
Author(s):  
Yuru Shang ◽  
Xianbin Zhang ◽  
Lili Lu ◽  
Ke Jiang ◽  
Mathias Krohn ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Viability ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immunoglobulin G ◽  
Cancer Cell Lines ◽  
Human Igg ◽  
Western Blots ◽  
Igg Receptors

Abstract Background Recent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics. Methods Influence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots. Results We evaluated the effects of pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity. Conclusions The present study demonstrates that pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.

miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP

2011 ◽  
Vol 69 (3) ◽  
pp. 723-731 ◽  
Author(s):  
Wei Zhu ◽  
Huaguo Xu ◽  
DanXia Zhu ◽  
Hui Zhi ◽  
Tongshan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines
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