Restoration of Taxol Sensitivity of Multidrug-Resistant Cells by the Cyclosporine SDZ PSC 833 and the Cyclopeptolide SDZ 280-446

Jachez, B; Nordmann, R.; Loor, Francis

doi:10.1093/jnci/85.6.478

Cited by 59 publications

(16 citation statements)

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“…[12][13][14][15] Furthermore, paclitaxel is a substrate for the MDR1/Pgp (Pglycoprotein) drug efflux pump overexpressed in various multidrugresistant cancer cells. 23,24 MDR1/Pgp expression has been detected in up to 41% of MM patient samples. [25][26][27] In contrast to paclitaxel, epothilones in general are equally cytotoxic against paclitaxelsensitive and paclitaxel-resistant human cancer cell lines, including those overexpressing MDR1/Pgp.…”

Section: Introductionmentioning

confidence: 99%

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

Lin

Catley

LeBlanc

et al. 2005

Blood

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Section: Introductionmentioning

confidence: 99%

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

Lin

Catley

LeBlanc

et al. 2005

Blood

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“…Taxanes are susceptible to several mechanisms of drug resistance. The first is the classic multidrug resistance gene product P-glycoprotein to pump the drugs out of the cells (5). The second is related to microtubule alterations, including mutations that result in changes in either microtubule dynamics or drug binding (6,7).…”

mentioning

confidence: 99%

Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates Antiapoptotic Proteins Bcl-XL and Survivin

Wang

et al. 2008

Clinical Cancer Research

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Purpose: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis. Experimental design: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance. Results: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxelinduced apoptosis. Conclusions: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.Prostate cancer is a serious threat to the health and quality of life of American men and is the second leading cause of cancerrelated death. Improvement in the efficacy of chemotherapy is urgently needed for patients with metastatic hormone refractory prostate cancer (HRPCa; ref. 1). The taxane drug docetaxel is the only Food and Drug Administration -approved chemotherapeutic agent for clinical treatment of advanced HRPCa. Two landmark studies (refs. 2,3; Southwest Oncology Group 9916 and TAX 327) provided the key support for this indication by demonstrating a modest survival advantage in HRPCa patients by using docetaxel-based combination chemotherapy.These studies supported taxane-based therapy as an attractive platform to develop new combinational regimens, which remain a high priority for many ongoing studies. A better understanding of the mechanisms of taxane resistance could provide a more rational strategy for the development of more effective taxane-based therapeutic combinations.Taxane drugs disrupt microtubule dynamics through direct binding to the h-subunit of tubulin, leading to mitotic arrest and eventual apoptosis (4). Taxanes are susceptible to several mechanisms of drug resistance. The first is the classic multidrug resistance gene product P-glycoprotein to pump the drugs out of the cells (5). The second is related to microtubule alte...

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“…PSC 833, a non-immunosuppressive cyclosporin is currently being tested as a chemosensitizer in myeloma and other malignancies. 3,10 In this study we show that for ex vivo myeloma cells, CsA, PSC 833, CsG or SDZ 280-446, a semisynthetic cyclopeptolide, 24,25 and some primary CsA and CsG metabolites effectively inhibit P-gp at concentrations expected to be achieved during in vivo infusion of chemosensitizers.…”

Section: Introductionmentioning

confidence: 65%

Drug resistance in multiple myeloma: cyclosporin A analogues and their metabolites as potential chemosensitizers

Pilarski¹,

Rw²,

Murphy³

et al. 1998

Leukemia

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In vivo, cyclosporins are rapidly and almost completely converted to metabolites. AM1 and AM4N, primary metabolites of CsA, mediated inhibition of transport, as did CsG metabolites GM1, GM4N and GM9. AM1 and GM9 are known to reach steady-state in vivo levels that exceed the inhibitory concentration identified here by 1.1-to 1.9-fold. Thus, cyclosporin metabolites, which accumulate in the blood during infusion of CsA and other cyclosporins, are shown here to be effective chemosensitizers for normally drugresistant myeloma cells in vitro. Cyclosporin metabolites are considered to be less toxic than the parent drugs, suggesting that novel chemosensitization strategies designed to minimize concentrations of parent drug and maximize accumulation of primary metabolites in vivo may optimize cytotoxicity to the malignant clone in myeloma.

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Restoration of Taxol Sensitivity of Multidrug-Resistant Cells by the Cyclosporine SDZ PSC 833 and the Cyclopeptolide SDZ 280-446

Cited by 59 publications

References 1 publication

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo

Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates Antiapoptotic Proteins Bcl-XL and Survivin

Drug resistance in multiple myeloma: cyclosporin A analogues and their metabolites as potential chemosensitizers

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