Molecular effects of paclitaxel: Myths and reality (a critical review)

Blagosklonny, Mikhail V.; Fojo, Tito

doi:10.1002/(sici)1097-0215(19991008)83:2<151::aid-ijc1>3.0.co;2-5

Cited by 324 publications

(245 citation statements)

References 64 publications

(62 reference statements)

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“…A plasma concentration of 5 -10 mM paclitaxel can be achieved after bolus infusion of paclitaxel, but it rapidly falls to a level of several hundred nanomolar or less. 42 Our experiments showed that 10 nM paclitaxel was sufficient to induce apoptosis in vitro in E1A-expressing cells but not in parental or vector control cells (Fig 1). This indicates that a clinically relevant concentration (5B200 nM) of paclitaxel is sufficient to kill E1A-expressing cells, but parental cells require much higher dosage, which may be difficult to be achieved in a clinical setting.…”

Section: Discussionmentioning

confidence: 83%

“…This indicates that a clinically relevant concentration (5B200 nM) of paclitaxel is sufficient to kill E1A-expressing cells, but parental cells require much higher dosage, which may be difficult to be achieved in a clinical setting. 42 We have previously shown that Her-2/neu-overexpressing cells are resistant to paclitaxel-induced apoptosis 43,44 and E1A, through downregulation of Her-2/neu, can sensitize cellular response to paclitaxel-induced apoptosis. 22,23,43,44 In those studies, we could not detect E1A-mediated chemosensitization in the low Her-2/neu-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

et al. 2004

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Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (Po.01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both Po.0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

et al. 2004

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“…Taxol and derivatives are used as potent drugs against several solid tumors. Although their cytotoxic mechanism depends on cell type, concentration and exposure duration, in most studies with clinically relevant taxol concentrations (10-200 nM), apoptosis is induced by blocking the mitotic spindle and a G2/M arrest (Schiff and Horwitz, 1980;Torres and Horwitz, 1998;Blagosklonny and Fojo, 1999;Zhao et al, 2005). The signaling pathways leading to cell death have been extensively studied (Blagosklonny and Fojo, 1999;Zhao et al, 2005) and recently several papers on the proteases involved were published.…”

Section: Introductionmentioning

confidence: 99%

“…Although their cytotoxic mechanism depends on cell type, concentration and exposure duration, in most studies with clinically relevant taxol concentrations (10-200 nM), apoptosis is induced by blocking the mitotic spindle and a G2/M arrest (Schiff and Horwitz, 1980;Torres and Horwitz, 1998;Blagosklonny and Fojo, 1999;Zhao et al, 2005). The signaling pathways leading to cell death have been extensively studied (Blagosklonny and Fojo, 1999;Zhao et al, 2005) and recently several papers on the proteases involved were published. It is now clear that taxol triggers apoptosis by both caspasedependent (Park et al, 2004;Ehrlichova et al, 2005;Li et al, 2005;Lu et al, 2005;Day et al, 2006;Janssen et al, 2007;Pineiro et al, 2007) and caspase-independent pathways (Broker et al, , 2004Huisman et al, 2002;Ofir et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insight into taxol-induced cell death

et al. 2008

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We analysed the involvement of proteases during taxolmediated cell death of human A549 non-small-cell lung carcinoma cells using a proteomics approach that specifically targets protein N termini and further detects newly formed N termini that are the result of protein processing. Our analysis revealed 27 protease-mediated cleavages, which we divided in sites C-terminal to aspartic acid (Asp) and sites C-terminal to non-Asp residues, as the result of caspase and non-caspase protease activities, respectively. Remarkably, some of the former were insensitive to potent pancaspase inhibitors, and we therefore suggest that previous inhibitor-based studies that report on the caspaseindependent nature of taxol-induced cell death should be judged with care. Furthermore, many of the sites C-terminal to non-Asp residues were also uniquely observed in a model of cytotoxic granule-mediated cell death and/or found by in vitro cataloging human l-calpain substrates using a similar proteomics technique. This thus raises the hypothesis that killing tumor cells by chemotherapy or by immune cells holds similar non-Asp-specific proteolytic components with strong indications to calpain activity.

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“…At clinically achievable concentrations from several hundred nanomolar to 3 mM, the best-characterized cellular target of paclitaxel are the microtubules (Blagosklonny and Fojo, 1999). In addition to its stabilizing effects on the microtubules and the subsequent cell cycle arrest in the G2-M phase, paclitaxel also induces the vast activation of signal-transduction pathways that may be associated with proapoptotic signaling (Blagosklonny and Fojo, 1999;Taxman et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Chan

Chen

et al. 2006

Oncogene

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Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 lM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 lM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 lM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

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Molecular effects of paclitaxel: Myths and reality (a critical review)

Cited by 324 publications

References 64 publications

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

Mechanistic insight into taxol-induced cell death

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

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