Effects of a new antioestrogen, idoxifene, on cisplatin- and doxorubicin-sensitive and -resistant human ovarian carcinoma cell lines

Sharp, Swee Y.; Rowlands, Martin; Jarman, Michael; Kèlland, Lloyd R.

doi:10.1038/bjc.1994.319

Cited by 22 publications

(13 citation statements)

References 20 publications

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“…The multidrug resistant efflux protein P-glycoprotein confers resistance to 17-AAG, as seen in the NCI 60 human cancer cell line panel (15) and using a human ovarian carcinoma cell line made resistant to doxorubicin, CH1doxR (27,44). Unlike 17-AAG but in common with CCT018159 (27), VER-49009 and VER-50589 each exhibited similar cellular GI 50 values in CH1doxR compared with parental CH1 cells (Table 1A).…”

Section: Growth-inhibitory Effects In Cell Lines With Acquired Drug Rmentioning

confidence: 90%

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Sharp

Prodromou

Boxall

et al. 2007

Molecular Cancer Therapeutics

139

103

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Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K d ) of VER-50589 was 4.5 F 2.2 nmol/L compared with 78.0 F 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC 50 of 21 F 4 nmol/L for VER-50589 compared with 47 F 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI 50 values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 F 15 and 685 F 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and Pglycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI 50 for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as

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Section: Growth-inhibitory Effects In Cell Lines With Acquired Drug Rmentioning

confidence: 90%

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Sharp

Prodromou

Boxall

et al. 2007

Molecular Cancer Therapeutics

139

103

View full text Add to dashboard Cite

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“…These cell lines have acquired resistance to cisplatin or doxorubicin through overexpression of MDR1 or MRP [74]. From the cDNA microarray studies carried out with 17AAG, no alteration of genes involved in drug efflux were identified [12].…”

Section: P-glycoprotein (Mdr1) and Multidrug Resistance Protein (Mrp)mentioning

confidence: 99%

Genes and Proteins Governing the Cellular Sensitivity to HSP90 Inhibitors: A Mechanistic Perspective

Maloney¹,

Clarke²,

Workman³

2003

CCDT

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HSP90 inhibitors such as 17AAG have the major therapeutic advantage that they exert downstream inhibitory effects on multiple oncogenic client proteins. They therefore block several mission critical cancer-causing pathways and have the potential to modulate all of the hallmark biological features of malignancy. Consistent with this combinatorial anti-oncogenic profile, 17AAG exhibits broad-spectrum antitumour activity against cultured cancer cell lines and in vivo animal models. However, there are clear differences in sensitivity between various cancer cell lines and it is quite possible that some tumour types or individual patients will be more responsive in the clinic than others. We describe the methods used to investigate the genes and proteins involved in the mechanism of action of HSP90 inhibitors and discuss the significance of these for cellular sensitivity. Methods used involve the conventional cell and molecular biology techniques, together with the more recent application of high throughput global technologies such as gene expression microarrays and proteomics. Selected examples that seem to play a role in sensitivity to HSP90 inhibitors are highlighted and the potential relevance to the response of cancer patients is discussed. Important determinants of response include: 1) Dependence upon key HSP90 client proteins such as ERBB2, steroid hormone receptors and AKT/PKB; 2) Levels of HSP90 family members and co-chaperones, such as HSP70 and AHA1; and 3) expression of various cell cycle and apoptotic regulators. In the case of 17AAG, metabolic enzymes such as NQO1 and membrane efflux pumps are also important for sensitivity.

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“…The human ovarian carcinoma cell line CH1 and its multidrug resistant variant CHIDoxR were used as negative and positive controls for P-glycoprotein expression and function (Sharp et al, 1994). The human non-small cell lung carcinoma cell line CORL23 and its multidrug resistant variant CORL23/R were used as negative and positive controls for MRP expression (Barrand et al, 1994).…”

Section: Cell Linesmentioning

confidence: 99%

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines

2000

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The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1 , mrp-1 and lrp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2 . The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance. © 2000 Cancer Research Campaign

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Effects of a new antioestrogen, idoxifene, on cisplatin- and doxorubicin-sensitive and -resistant human ovarian carcinoma cell lines

Cited by 22 publications

References 20 publications

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Genes and Proteins Governing the Cellular Sensitivity to HSP90 Inhibitors: A Mechanistic Perspective

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines

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