Intrinsic chemotherapy resistance to the tubulin‐binding antimitotic agents in renal cell carcinoma

Ferguson, Roisean E.; Jackson, Sharon M.; Stanley, Anthea J.; Joyce, Adrian; Harnden, Patricia; Morrison, Ewan E.; Patel, Poulam M.; Phillips, Roger M.; Selby, Peter J.; Banks, Rosamonde E.

doi:10.1002/ijc.20816

Cited by 23 publications

(20 citation statements)

References 42 publications

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“…Ferguson et al suggest from patient data that, in renal cell carcinomas, MVP expression might be a more important indicator of drug resistance than ATP-binding cassette transporter pumps. Surprisingly, in a panel of cell lines from the same tumor origin, the opposite is true, and the expression levels of ATP-binding cassette transporter pumps is most indicative of the sensitivity to the antineoplastic drugs (45). This not only indicates what has been reported at many separate occasions previously, that MVP protein expression is indeed important for drug response in vivo, but also indicates that this phenotype translates poorly to the in vitro situation.…”

Section: Discussionmentioning

confidence: 73%

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Herlevsen

Oxford

Owens

et al. 2007

Molecular Cancer Therapeutics

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The major vault protein (MVP) is the major constituent of the vault particle, the largest known ribonuclear protein complex. To date, vaults have no clear function, although their low expression levels in de novo chemosensitive and curable tumors, such as testicular cancer, make them attractive candidates as contributors to intrinsic drug resistance. Here, we show that MVP knockdown in human bladder cancer cells via small interfering RNA results in sensitization toward doxorubicin in two distinct exposure protocols. The drug was detected in the nucleus immediately following addition and was subsequently sequestered to lysosomes, predominantly located adjacent to the nucleus. MVP knockdown leads to increased sensitivity toward doxorubicin and an enhanced nuclear accumulation of the drug as well as a loss of its perinuclear sequestration. Not only doxorubicin subcellular distribution was perturbed by MVP knockdown but lysosomal markers, such as pH-sensitive LysoSensor, pinocytosed dextran conjugates after 24-h chase period, and the lysosomal specific antigen Lamp-1, also showed a markedly different staining compared with controls. Lysosomes appeared dispersed through the cytoplasm without a clear organization adjacent to the nucleus. Microtubules, however, appeared unperturbed in cells with reduced MVP expression. Based on these data, we hypothesize that MVP and, by extension, vault complexes are important for lysosomal function and may influence cellular drug resistance by virtue of this role. [Mol Cancer Ther 2007;6(6):1804 -13]

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Section: Discussionmentioning

confidence: 73%

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Herlevsen

Oxford

Owens

et al. 2007

Molecular Cancer Therapeutics

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“…One class of these compounds receiving particular attention has been that based on the natural product combretastatin A-4 discovered by Pettit [10,11]. Despite some successes, the discovery of new, more efficacious inhibitors is becoming increasingly important because of multi-drug resistance to tubulin-binding antimitotic agents [12]. Furthermore, chemical synthesis of combretastatin analogues is multi-step and difficult.…”

Section: Introductionmentioning

confidence: 99%

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Tripathi

Fornabaio

Kellogg

et al. 2008

Bioorganic & Medicinal Chemistry

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Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for eighteen polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of αβ-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r 2 of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.

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“…Cell lines were routinely cultured in RPMI 1640 supplemented with 1% v/v L-glutamine and 10% FCS at 37jC in 5% CO 2 . The IC 50 (defined as the drug concentration that resulted in a 50% reduction in cell viability in drug-treated wells relative to control wells) of these cell lines for paclitaxel has been reported previously (8).…”

Section: Methodsmentioning

confidence: 52%

“…Several potential mechanisms of TBA drug resistance in cancers have been suggested including increased drug efflux due to overexpression of the membrane transporter, P-glycoprotein (MDR-1). However, our previous studies did not find any relationship between expression of P-glycoprotein and response to paclitaxel, vinblastine, and epothilone-B in a panel of RCC cell lines and P-glycoprotein expression in RCC tissue was decreased compared with normal kidney tissue (8). Other possible mechanisms may include alterations of the h-tubulin target (9) resulting in changes in microtubule dynamics, such as may arise from altered expression of tubulin isotypes (10 -12), tubulin mutations (13), and altered expression or binding of microtubule-regulatory proteins (14).…”

mentioning

confidence: 77%

“…To gain some insight into the possible effect of such increased class I expression in RCC on chemoresistance, we examined class I and III expression levels in a panel of established RCC cell lines with a broad range in intrinsic resistance to the TBAs (8). A significant correlation in expression of class III tubulin and resistance to vinblastine only was observed.…”

Section: Discussionmentioning

confidence: 99%

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Resistance to the Tubulin-Binding Agents in Renal Cell Carcinoma: No Mutations in the Class I β-Tubulin Gene but Changes in Tubulin Isotype Protein Expression

Ferguson

Taylor

Stanley

et al. 2005

Clinical Cancer Research

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Purpose:The primary purpose of this study was to determine whether mutations of the class I b-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III h-tubulin isotype protein expression. Experimental Design: DNA was extracted from 90 renal tumors and the class I b-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III h-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to theTBAs was examined by Western blotting. Results: Four polymorphic sequence changes of the class I b-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed. Conclusions:These results do not support a role for mutations in the class I b-tubulin gene in the intrinsic resistance of renal cancer toTBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to theTBAs and warrants further investigation.

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Intrinsic chemotherapy resistance to the tubulin‐binding antimitotic agents in renal cell carcinoma

Cited by 23 publications

References 42 publications

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes

Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity

Resistance to the Tubulin-Binding Agents in Renal Cell Carcinoma: No Mutations in the Class I β-Tubulin Gene but Changes in Tubulin Isotype Protein Expression

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