In vivo establishment and characterization of a paclitaxel-resistant human ovarian cancer cell line showing enhanced growth properties and drug-resistance only in vivo

Okugawa, Kaoru; Kobayashi, Hiroaki; Hirakawa, Tsubasa; Sonoda, T.; Ogura, Tomohito; Nakano, Hitoo

doi:10.1007/s00432-003-0516-9

Cited by 11 publications

(3 citation statements)

References 17 publications

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“…In addition, ABC drug transporter family proteins [ 8 ] and clusterin [ 7 , 9 ], have been proposed to play a role in resistance. Accumulating evidence suggests that more aggressive disease develops after DTX-resistance [ 11 , 12 ] with recruitment and activation of cancer stem [ 13 , 14 ]. In breast cancer, it was recently shown that residual cancer cells increased mammosphere formation efficacy when compared to primary cancers [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

et al. 2017

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Background and aimsDocetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon.Material and methodsHere, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their. DTX resistant derivatives.Results and conclusionsWe show that DTX resistance may involve overexpression of β-III tubulin (TUBB3) and P-glycoprotein as well as increased cytoplasmic accumulation of Foxo3a. Increased levels of XPO-1 were also observed in DTX resistant cells suggesting that SINE compounds may modulate DTX effectiveness in sensitive cells as well as restore the sensitivity to DTX in resistant ones. Pretreatment with SINE compounds, indeed, sensitized to DTX through increased tumor shrinkage and apoptosis by preventing DTX-induced cell cycle arrest. Basally SINE compounds induce FOXO3a activation and nuclear accumulation increasing the expression of FOXO-responsive genes including p21, p27 and Bim causing cell cycle arrest. SINE compounds-catenin and survivin supporting apoptosis. βdown-regulated Cyclin D1, c-myc, Nuclear sequestration of p-Foxo3a was able to reduce ABCB1 and TUBB3 H2AX levels, prolonged γ expression. Selinexor treatment increased DTX-mediated double strand breaks (DSB), and reduced the levels of DNA repairing proteins including DNA PKc and Topo2A. Our results provide supportive evidence for the therapeutic use of SINE compounds in combination with DTX suggesting their clinical use in mCRPC patients.

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Section: Introductionmentioning

confidence: 99%

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

et al. 2017

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“…Similar approaches have been employed by others to establish drug-resistant cell lines (Okugawa et al , 2004; Starling et al , 1990; Teicher et al , 1990). Interestingly, contrary to our model, resistance was not maintained when the established cell lines were exposed to paclitaxel in vitro in these models.…”

Section: Discussionmentioning

confidence: 88%

miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo

et al. 2011

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Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized miRNA arrays to screen for differentially expressed miRNAs in paclitaxel-resistant cell lines established in vitro. We observed concordant upregulation of miR-135a in paclitaxel-resistant cell lines representing three human malignancies. Subsequently, the role of miRNA-135a was evaluated in an in vivo model of paclitaxel resistance. In this model, mice were inoculated subcutaneously with a non-small cell lung carcinoma cell line and treated with paclitaxel for a prolonged period. In paclitaxel-resistant cell lines, established either in vitro or in vivo, blockage of miR-135a sensitized resistant cell lines to paclitaxel-induced cell death. We further demonstrated a correlation between paclitaxel response and miR-135a expression in paclitaxel-resistant subclones that were established in vivo. The paclitaxel-resistant phenotype of these subclones was maintained upon retransplantation in new mice as shown by decreased tumor response upon paclitaxel treatment compared to controls. Upregulation of miR-135a was associated with reduced expression of the adenomatous polyposis coli gene (APC). APC knockdown increased paclitaxel resistance in parental cell lines. Our results indicate that paclitaxel resistance is associated with upregulation of miR-135a both in vitro and in vivo, and is in part mediated by miR-135a-mediated downregulation of APC.

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“…However these cells usually show strongly suppressed metastatic and/or tumorigenic properties in vivo which makes them incompatible comparators to recurrent cancers which show increased metastatic and/or tumor growth potential. Several groups have reported development of xenograft resistant models by administration of PTX in a subcutaneous model followed by excision and re-transplantation over 6 months and the final tumor-derived cells being established and maintained as in vivo resistance sublines (24). In the current study we aimed to develop in vivo PTX resistance by repeated administration of PTX to recapitulate clinical resistance development and assess the effectiveness of our therapies in these models.…”

Section: Discussionmentioning

confidence: 99%

Cosilencing of PKM-2 and MDR-1 Sensitizes Multidrug-Resistant Ovarian Cancer Cells to Paclitaxel in a Murine Model of Ovarian Cancer

Talekar

Ouyang

Goldberg

et al. 2015

Molecular Cancer Therapeutics

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Tumor multidrug resistance (MDR) is a serious clinical challenge that significantly limits the effectiveness of cytotoxic chemotherapy. As such, complementary therapeutic strategies are being explored to prevent relapse. The altered metabolic state of cancer cells, which perform aerobic glycolysis, represents an interesting target that can enable discrimination between healthy cells and cancer cells. We hypothesized that co-silencing of genes responsible for aerobic glycolysis and for MDR would have synergistic antitumor effect. In the current study, siRNA duplexes against pyruvate kinase M2 (siPKM-2) and multidrug resistance gene-1 (siMDR-1) were encapsulated in hyaluronic acid (HA)-based self-assembling nanoparticles. The particles were characterized for morphology, size, charge, encapsulation efficiency and transfection efficiency. In vivo studies included biodistribution assessment, gene knockdown confirmation, therapeutic efficacy, and safety analysis. The benefit of active targeting of cancer cells was confirmed by modifying the particles’ surface with a peptide targeted to epidermal growth factor receptor (EGFR), which is overexpressed on the membranes of the SKOV-3 cancer cells. To augment the studies involving transplantation of a PTX-resistant cell line, an in vivo paclitaxel (PTX) resistance model was developed by injecting repeated doses of PTX following tumor inoculation. The nanoparticles accumulated significantly in the tumors, hindering tumor volume doubling time (p<0.05) upon combination therapy in both the wild type (2-fold) and resistant (8-fold) xenograft models. Whereas previous studies indicated that silencing of MDR-1 alone sensitized MDR ovarian cancer to PTX only modestly, these data suggest that concurrent silencing of PKM-2 improves the efficacy of PTX against MDR ovarian cancer.

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In vivo establishment and characterization of a paclitaxel-resistant human ovarian cancer cell line showing enhanced growth properties and drug-resistance only in vivo

Cited by 11 publications

References 17 publications

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo

Cosilencing of PKM-2 and MDR-1 Sensitizes Multidrug-Resistant Ovarian Cancer Cells to Paclitaxel in a Murine Model of Ovarian Cancer

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