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Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A

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Summary

Chemotherapeutic agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-stabilizing agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another stabilizing agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-stabilizing agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging agent, paclitaxel, and discodermolide were used as positive controls. Senescence-associated-β-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > discodermolide > peloruside, based on IC25 concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-stabilizing agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line.

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Abbreviations

DDR:

DNA damage response

Disco:

Discodermolide

Doxo:

Doxorubicin

MSA:

Microtubule stabilizing agent

MTA:

Microtubule targeting agent

OIS:

Oncogene-induced senescence

PelA:

Peloruside A

Ptx:

Paclitaxel

SA-β-gal:

Senescence associated β-galactosidase

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Author information

Authors and Affiliations

  1. Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand

    Ariane Chan, Connie Gilfillan, Nikki Templeton & John H. Miller

  2. Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand

    Ariane Chan, Connie Gilfillan, Nikki Templeton, Peter T. Northcote & John H. Miller

  3. Volpara Health Technologies Limited, Level 12, 86 Victoria Street, Wellington, 6011, New Zealand

    Ariane Chan

  4. Department of Chemistry, Cambridge University, Cambridge, CB2 1EW, UK

    Ian Paterson

  5. Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand

    Peter T. Northcote

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  1. Ariane Chan
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  2. Connie Gilfillan
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  3. Nikki Templeton
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  4. Ian Paterson
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  5. Peter T. Northcote
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Contributions

A.C. and J.H.M. conceived and designed the experiments; A.C. performed the experiments; A.C. analyzed the data with assistance from J.H.M., C.G. and N.T.; P.T.N. provided the peloruside A; I.P. provided the discodermolide; A.C. and J.H.M. initially wrote the paper; C.G., N.T., P.T.N. and I.P. contributed to the editing and critical evaluation of the manuscript.

Corresponding author

Correspondence to John H. Miller.

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Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

Peter Northcote and John Miller are named on a 2004 US patent for development of peloruside A as an anticancer agent. Ariane Chan, Connie Gilfillan, Nikki Templeton, and Ian Paterson declare that they have no conflict of interest.

Funding

This research was supported by grant E1807 from the Cancer Society of New Zealand to JHM, PTN, and AC, grant E1707 from the Wellington Medical Research Foundation to JHM and PTN, and grant UGC-204067 from Victoria University of Wellington to JHM and PTN. AC was the recipient of PhD Scholarship E1802 from the Genesis Oncology Trust of New Zealand.

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Chan, A., Gilfillan, C., Templeton, N. et al. Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A. Invest New Drugs 35, 706–717 (2017). https://doi.org/10.1007/s10637-017-0493-5

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