Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells

Wilmes, Anja; O’Sullivan, David; Chan, Ariane; Chandrahasen, Clarissa; Paterson, Ian; Northcote, Peter T.; Flamme, Anne Camille La; Miller, John H.

doi:10.1007/s00280-010-1461-3

Cited by 34 publications

(46 citation statements)

References 33 publications

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“…9,12 In addition, laulimalide can displace bound peloruside A, 8 and laulimalide and peloruside A are not synergistic in combination with each other, but only with paclitaxel binding site ligands. 11 These results indicated that peloruside A and laulimalide likely share a new binding site, distinct from the paclitaxel site, and possibly act via mechanisms of stabilization distinct from paclitaxel. This binding site is the second for stabilizing drugs, and the fourth of the four mentioned above.…”

Section: Introductionmentioning

confidence: 85%

“…This is known from studies that indicate synergy between peloruside A or laulimalide and other microtubulestabilizing drugs, all of which bind at the paclitaxel binding site, [9][10][11]23 as well as from direct binding studies that have shown that microtubules formed in vitro and taxol-saturated can still bind peloruside A and vice-versa. 8,21 These results demonstrated that the binding site for peloruside A and laulimalide was a new drug site on tubulin, but did not indicate where on tubulin it might be.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

“…This conclusion was reached due to evidence that peloruside A does not displace paclitaxel from MT, and does act synergistically with paclitaxel in cell-based assays. [8][9][10][11] The macrolide laulimalide shares these properties with peloruside A. 9,12 In addition, laulimalide can displace bound peloruside A, 8 and laulimalide and peloruside A are not synergistic in combination with each other, but only with paclitaxel binding site ligands.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

Begaye¹,

Trostel²,

Zhao³

et al. 2011

Cell Cycle

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Section: Introductionmentioning

confidence: 85%

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

Begaye¹,

Trostel²,

Zhao³

et al. 2011

Cell Cycle

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“…These include dose-limiting toxicities (3-5) and problems with vehicle (31). Synergistic interactions between peloruside and the taxane site drugs have been previously described in vitro in cultured cancer cell lines (32,33).…”

Section: Properties Of Pelorusidementioning

confidence: 99%

“…Peloruside at 5 mg/kg in combination with docetaxel at 6.3 mg/kg gave a TGI of 99%, a value greater than the single-agent values for peloruside of 88% and docetaxel of 19%, suggesting possible synergistic interactions between the 2 MSAs. Because different concentrations of peloruside and taxanes were not tested on tumor growth in vivo, a true synergy calculation was not able to be carried out (32,33).…”

Section: Properties Of Pelorusidementioning

confidence: 99%

Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model

Meyer

Krauth

Wick³

et al. 2015

Molecular Cancer Therapeutics

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Peloruside A is a microtubule-stabilizing agent isolated from a New Zealand marine sponge. Peloruside prevents growth of a panel of cancer cell lines at low nanomolar concentrations, including cell lines that are resistant to paclitaxel. Three xenograft studies in athymic nu/nu mice were performed to assess the efficacy of peloruside compared with standard anticancer agents such as paclitaxel, docetaxel, and doxorubicin. The first study examined the effect of 5 and 10 mg/kg peloruside (QDÂ5) on the growth of H460 non-small cell lung cancer xenografts. Peloruside caused tumor growth inhibition (%TGI) of 84% and 95%, respectively, whereas standard treatments with paclitaxel (8 mg/kg, QDÂ5) and docetaxel (6.3 mg/kg, Q2DÂ3) were much less effective (%TGI of 50% and 18%, respectively). In a second xenograft study using A549 lung cancer cells and varied schedules of dosing, activity of peloruside was again superior compared with the taxanes with inhibitions ranging from 51% to 74%, compared with 44% and 50% for the two taxanes. A third xenograft study in a P-glycoprotein-overexpressing NCI/ADR-RES breast tumor model showed that peloruside was better tolerated than either doxorubicin or paclitaxel. We conclude that peloruside is highly effective in preventing the growth of lung and P-glycoprotein-overexpressing breast tumors in vivo and that further therapeutic development is warranted.

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Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

Wullschleger

Gertsch

Altmann

2013

Chemistry A European J

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The stereoselective syntheses of 7,8,9-trideoxypeloruside A (4) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety (3) are described. The syntheses proceeded through the PMB-ether of an ω-hydroxy β-keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3-syn and -anti diols by stereoselective Duthaler-Hafner allylations and subsequent 1,3-syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high-yielding Prins reaction, to provide the precursor for bicyclic analogue 4. Downstream steps for both syntheses included the substrate-controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring-closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi-type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub-micromolar IC50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.

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Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells

Cited by 34 publications

References 33 publications

Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

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