Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

Galletti, Elena; Magnani, Matteo; Renzulli, Michela L.; Botta, Maurizio

doi:10.1002/cmdc.200600308

Cited by 154 publications

(116 citation statements)

References 161 publications

(155 reference statements)

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“…Silencing of PHB1 renders cells sensitive to paclitaxel both in vitro and in vivo. We do not propose that PHB1 is the only modulator of taxane sensitivity in human cancers as other mediators have been reported including increased levels of GSTπ (6,43,44) (confirmed in this study), tubulin mutations, and alterations in the MDR pathway (4,5). For some tumors, however, alterations in PHB1 levels or interference with PHB1 localization may result in increased sensitivity of human tumors to taxane treatment.…”

Section: Discussionmentioning

confidence: 40%

“…Several molecular mechanisms of paclitaxel resistance have been suggested in vitro. These include the expression of the multidrug resistance (MDR) phenotype and alterations in the microtubule system (4,5). However, attempts to extend these in vitro data to identify useful clinical markers of paclitaxel resistance and to develop other therapeutic strategies to reverse paclitaxel resistance are still ongoing or have yielded disappointing results.…”

mentioning

confidence: 99%

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Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Patel

Chatterjee

Vrbanac

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GSTπ were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTπ gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTπ resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTπ significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.apoptosis | glutathione-S-transferase Pi | mitochondria | plasma membrane | protein translocation

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Section: Discussionmentioning

confidence: 40%

mentioning

confidence: 99%

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Patel

Chatterjee

Vrbanac

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Unfortunately, over time, most patients still progress to develop resistance to docetaxel. Much of this resistance is thought to be mediated through expression of the multidrug-resistance transporter, P-glycoprotein or by microtubule alterations (21). In addition to inducing apoptosis in a variety of cancerous cell types (5-9) and impairing tumour growth in vivo (11,12), novel pyrrolo-1,5-benzoxazepine (PBOX) compounds possess the added benefit of inducing cytotoxicity in multidrug-resistant cancer cells expressing P-glycoprotein with similar potency as in P-glycoprotein-negative cancer cells (14).…”

Section: Discussionmentioning

confidence: 99%

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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Abstract. Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce antiproliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G 2 /M arrest. G 2 /M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of antiapoptotic proteins Bcl-2 and Bcl-x L and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G 2 /M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-x L . Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOXinduced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer. IntroductionProstate cancer is the leading cause of cancer and the second leading cause of cancer-related deaths among men in Europe and the USA (1). Early diagnosis following widespread PSA screening has resulted in most patients presenting with localized tumours. These patients generally exhibit good survival rates following radiotherapy or surgery. However, a number of patients still progress to or are diagnosed with locally advanced or metastatic tumours. While androgendeprivation therapy can slow the development of advanced metastatic prostate cancer, most tumours will still progress within a few years to an androgen-independent state (2). At this stage, treatment options become limited. The current treatment of choice for patients with advanced hormonerefractory prostate cancer is docetaxel-based chemotherapy. While these treatments significantly improve the overall survival of patients (3,4), the prognosis still remains poor for patients presenting with advanced stage prostate cancer. Therefore, the development of improved treatments and combinations are required.Our research group have established that some members of the pyrrolo-1,5-benzoxazepine (PBOX) famil...

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“…The expression of the multidrug resistance (MDR) phenotype is a main mechanism involved in resistance to taxanes (9)(10)(11)(12). ABCB1 (P-glycoprotein) is an ATP-binding cassette (ABC) drug pump (13), and is currently the most extensively studied MDR-related transporter protein (14,15), mediating the ATP-dependent efflux of a wide range of hydrophobic drugs such as taxanes (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

et al. 2017

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Abstract. Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxel-resistant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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Paclitaxel And Docetaxel Resistance: Molecular Mechanisms and Development of New Generation Taxanes

Cited by 154 publications

References 161 publications

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

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