Overcoming Multidrug Resistance in Taxane Chemotherapy

Geney, Raphaël; Ungureanu, loana Maria; Li, Dansu; Ojima, Iwao

doi:10.1515/cclm.2002.161

Cited by 69 publications

(49 citation statements)

References 30 publications

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“…Paclitaxel has low water solubility (13) and has limited brain distribution primarily due to the BBB efflux transporter, P-gp (10,45,46). Several strategies have been used to circumvent P-gp at BBB, including chemical modification, (47) encapsulating in nanoparticles (48), and conjugating to peptide vectors (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate ($5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G 2 -M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC 50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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“…Tumor cells for example can develop resistance to antimitotic inhibitors that target tubulin such as taxanes and vinca alkaloids [42] through mutations in the drug binding site (i.e.  tubulin) [43,44] or by overexpression of the drug efflux pump, P-glycoprotein [45]. The ability to confer drug resistance by introducing mutations in the induced fit binding pocket of Eg5 raises the possibility that such mutations may be encountered in tumors during chemotherapy if Eg5 inhibitors were to enter the clinic.…”

Section: Monastrol and Stlc Have Been Characterized As Eg5 Specific Imentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

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. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

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“…As a result of these important new studies, docetaxel is currently the drug of choice in prostate cancer chemotherapy. Unfortunately, clinical treatment with docetaxel often encounters a number of undesirable side effects, including drug resistance (Miller and Ojima, 2001;Geney et al, 2002;Petrylak, 2005). Therefore, it has become essential to identify molecular events that may be associated with the development of docetaxel resistance.…”

Section: Introductionmentioning

confidence: 99%

Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells

et al. 2006

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A major obstacle for clinicians in the treatment of advanced prostate cancer is the inevitable progression to chemoresistance, especially to docetaxel. It is essential to understand the molecular events that lead to docetaxel resistance in order to identify means to prevent or interfere with chemoresistance. In initial attempts to detect these events, we analysed genomic differences between non-resistant and docetaxel-resistant prostate tumor cells and, of the genes modulated by docetaxel treatment, we observed Stat1 and clusterin gene expression heightened in the resistant phenotype. In this study, we provide biochemical and biological evidence that these two gene products are related. Stat1 and clusterin protein expression was induced upon docetaxel treatment of DU145 cells and highly overexpressed in the docetaxelresistant DU145 cells (DU145-DR). The increase in total Stat1 corresponded to an increase in phosphorylated Stat1. Interestingly, there was no detectable difference between DU145 and DU145-DR cells expression of total Stat3 and phosphorylated Stat3. Treatment of DU145-DR cells with small interfering RNA targeted for Stat1 not only resulted in the knockdown of Stat1 expression, but it also caused the inhibition of clusterin expression. Thus, Stat1 appears to play a key role in the regulation of clusterin. Remarkably, inhibition of Stat1 or clusterin expression resulted in the re-sensitization of DU145-DR cells to docetaxel. These results offer the first evidence that Stat1, and its subsequent regulation of clusterin, are essential for docetaxel resistance in prostate cancer. Targeting this pathway could be a potential therapeutic means for intervention of docetaxel resistance.

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Overcoming Multidrug Resistance in Taxane Chemotherapy

Cited by 69 publications

References 30 publications

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells

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