Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer

Bo Gao, Amanda Russell, Jonathan Beesley, Xiao Qing Chen, Sue Healey, Michelle Henderson, Mark Wong, Catherine Emmanuel, Laura Galletta, Sharon E. Johnatty, David Bowtell, Michelle Haber, Murray Norris, Paul Harnett, Georgia Chenevix-Trench, Rosemary L. Balleine, Anna Defazio, Dorota Gertig, Adèle Green, Penelope WebbJillian Hung, Sue Moore, Nadia Traficante, Sian Fereday, Karen Harrap, Troy Sadkowsky, Nirmala Pandeya, Robin Stuart-Harris, Fred Kirsten, Josie Rutovitz, Peter Clingan, Amanda Glasgow, Anthony Proietto, Stephen Braye, Greg Otton, Jennifer Shannon, Tony Bonaventura, James Stewart, Stephen Begbie, Michael Friedlander, David Bell, Sally Baron-Hay, Alan Ferrier, Greg Gard, David Nevell, Nick Pavlakis, Sue Valmadre, Barbara Young, Catherine Camaris, Roger Crouch, Lyndal Edwards, Neville Hacker, Donald Marsden, Greg Robertson, Phillip Beale, Jane Beith, Jonothan Carter, Chris Dalrymple, Anne Hamilton, Roger Houghton, Peter Russell, Matthew Links, John Grygiel, Jane Hill, Alison Brand, Karen Byth, Richard Jaworski, Raghwa Sharma, Anita Achen, Gerard Wain, Bruce Ward, David Papadimos, Alex Crandon, Margaret Cummings, Ken Horwood, Andreas Obermair, Lew Perrin, David Wyld, Jim Nicklin, Margaret Davy, Martin K. Oehler, Chris Hall, Tom Dodd, Tabitha Healy, Ken Pittman, Doug Henderson, John Miller, John Pierdes, Penny Blomfield, David Challis, Robert McIntosh, Andrew Parker, Bob Brown, Robert Rome, David Allen, Peter Grant, Simon Hyde, Rohan Laurie, Melissa Robbie, David Healy, Tom Jobling, Tom Manolitsas, Jane McNealage, Peter Rogers, Beatrice Susil, Eric Sumithran, Ian Simpson, Kelly Phillips, Danny Rischin, Stephen Fox, Daryl Johnson, Paul Waring, Stephen Lade, Maurice Loughrey, Neil O'Callaghan, William Murray, Virginia Billson, Jan Pyman, Debra Neesham, Michael Quinn, Craig Underhill, Richard Bell, Leong Fook Ng, Robert Blum, Vinod Ganju, Ian Hammond, Yee Leung, Anthony McCartney, Martin Buck, Izak Haviv, David Purdie, David Whiteman, Nikolajs Zeps, Mary Rose Malt, Anne Mellon, Randall Robertson, Trish Vanden Bergh, Marian Jones, Patricia Mackenzie, Jane Maidens, Kath Nattress, Yoke Eng Chiew, Annie Stenlake, Helen Sullivan, Barbara Alexander, Pat Ashover, Sue Brown, Tracy Corrish, Lyn Green, Leah Jackman, Kaltin Ferguson, Karen Martin, Adam Martyn, Barbara Ranieri, Jo White, Victoria Jayde, Leanne Bowes, Pamela Mamers, Debra Giles, Joy Hendley, Katherine Alsop, Trudy Schmidt, Helen Shirley, Colleen Ball, Cherry Young, Suzanna Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.

Original languageEnglish
Article number4669
JournalScientific Reports
Volume4
DOIs
StatePublished - 9 May 2014
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported by the National Health and Medical Research Council (NHMRC) of Australia (scholarship to B.G.), Cancer Institute New South Wales and Cancer Australia (552481). AdeF is funded by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre. We gratefully acknowledge the cooperation of the institutions that supported the study. We also acknowledge the contribution of Australian Ovarian Cancer Study Group (full list can be found at http://www.aocstudy.org), all study nurses and research assistants and would like to thank all of the women who participated in AOCS. AOCS was supported by U.S. Army Medical Research and Materiel Command DAMD17-01-1-0729, NHMRC Enabling Grant 400413 and Project Grant 400281, the Cancer Council Tasmania and the Cancer Foundation of Western Australia.

Funding

This project was supported by the National Health and Medical Research Council (NHMRC) of Australia (scholarship to B.G.), Cancer Institute New South Wales and Cancer Australia (552481). AdeF is funded by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre. We gratefully acknowledge the cooperation of the institutions that supported the study. We also acknowledge the contribution of Australian Ovarian Cancer Study Group (full list can be found at http://www.aocstudy.org), all study nurses and research assistants and would like to thank all of the women who participated in AOCS. AOCS was supported by U.S. Army Medical Research and Materiel Command DAMD17-01-1-0729, NHMRC Enabling Grant 400413 and Project Grant 400281, the Cancer Council Tasmania and the Cancer Foundation of Western Australia.

FundersFunder number
Cancer Foundation of Western Australia
Cancer Institute New South Wales and Cancer Australia552481
Sydney-West Translational Cancer Research Centre
Medical Research and Materiel CommandDAMD17-01-1-0729
National Health and Medical Research Council400281, 400413
Cancer Council Tasmania
Cancer Institute NSW
University of Sydney

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