Cellular Mechanisms of Resistance to Anthracyclines and Taxanes in Cancer: Intrinsic and Acquired

Chien, A. Jo; Moasser, Mark M.

doi:10.1053/j.seminoncol.2008.02.010

Cited by 67 publications

(52 citation statements)

References 126 publications

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“…P-glycoprotein is an ATP-dependent efflux transporter belonging to the ATP-binding cassette transporter superfamily. It mediates drugabsorption and excretion and is one mechanism of chemotherapy resistance, as its activity decreases uptake of chemotherapeutic agents in some cancer cells [55,56]. P-glycoprotein is present in many normal human tissues, most notably the luminal membrane of enterocytes and the apical membrane of both hepatocytes and renal tubular cells [57].…”

Section: Drug-drug Interactions Of the Noacsmentioning

confidence: 99%

New Oral Anticoagulants and the Cancer Patient

Short¹,

2013

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Section: Drug-drug Interactions Of the Noacsmentioning

confidence: 99%

New Oral Anticoagulants and the Cancer Patient

Short¹,

2013

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“…Docetaxel is indicated for first-line treatment of breast, head and neck, gastric, lung, and prostate cancer and for secondline treatment of breast cancer (7). However, the use of both paclitaxel and docetaxel is limited by the development of tumor resistance (8)(9)(10). During the last 2 decades, considerable efforts have been made to understand, and develop new agents to overcome, taxane resistance.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors

Vrignaud

Semiond

Lejeune

et al. 2013

Clinical Cancer Research

201

191

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Purpose: Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.Experimental Design: Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapyresistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.Results: In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC 50 ranges: cabazitaxel, 0.013-0.414 mmol/L; docetaxel, 0.17-4.01 mmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).Conclusions: Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.

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“…11 Besides alteration in the expression of tubulin or microtubuleassociated proteins and multidrug resistance, dysregulation of cellular pathways such as cell cycle control, cell proliferation, apoptosis and nuclear-cytoplasmic transport have been linked to taxane activity and resistance. 12 Numerous studies provide evidence that SAC has a role in taxane response, either enhancing sensitivity to these spindle toxins 13,14 or increasing mitotic arrest or 'resistance'. 15,16 Aurora-A kinase has been linked to taxane resistance; 17 it is amplified in breast cancer, 18 overexpressed in several tumors with poor prognosis and it is an emerging therapeutic target.…”

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USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

et al. 2013

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A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.

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Cellular Mechanisms of Resistance to Anthracyclines and Taxanes in Cancer: Intrinsic and Acquired

Cited by 67 publications

References 126 publications

New Oral Anticoagulants and the Cancer Patient

New Oral Anticoagulants and the Cancer Patient

Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors

USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

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