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Peter W. Gout, Ph.D

 

Tel: 604-675-8000 ext. 7012

Fax: 604-675-8019

 

Research Role:

  • Research Development Facilitator
  • Retired Head, Department of Cancer Endocrinology, BCCA, March 2004 
  • Honorary Senior Research Scientist, Department of Cancer Endocrinology, BCCA
  • Honorary Associate Professor, Urologic Sciences, UBC

 

Education:

  • Ph.D. (Biochemistry), State University of Leiden, The Netherlands, 1984

  • M.Sc. (Biochemistry), State University of Leiden, The Netherlands, 1964



Personal Interests:

Loves taking pictures

 

Research Interests:

My current interest is focused on a new way to improve chemotherapy of difficult to treat malignancies, including advanced cancers of the pancreas, prostate and lymphoid tissue. It involves inhibition of the function of a transporter molecule, designated xc-, which plays an important role in maintaining viability and drug resistance of cancer cells 1.

Glutathione is a major antioxidant considered essential for protection of cells from oxidative stress. It also plays an important role as a detoxifier and is known to underlie drug resistance. Oxidative stress is particularly generated in cancer cells due to their relatively high metabolism, and glutathione depletion has been suggested as a therapeutic approach for a variety of cancers, in particular to reduce resistance to conventional anticancer agents 1. Intracellularly, glutathione is mainly present in the reduced form (GSH), i.e. a linear tripeptide thiol with a short half-life, consisting of glutamate, cysteine and glycine. Cysteine is a rate-limiting precursor of GSH and sustenance of adequate intracellular cysteine levels is critical for maintaining adequate GSH levels, cell growth and viability. For some cancers this depends on uptake of cysteine or cystine (the oxidized form of the amino acid) from their microenvironment, as indicated by cystine/cysteine growth requirements of cell lines derived from e.g., lymphomas and pancreatic cancers 1-3. There is substantial evidence suggesting that the xc- plasma membrane cystine/glutamate antiporter plays an important role in the maintenance of intracellular cysteine/cystine levels by mediating (i) direct uptake of cystine 2 and (ii) in vivo supply of cysteine by stromal cells (e.g., activated macrophages, fibroblasts) 4. Such somatic cells can pick up cystine, the predominant form in the extracellular compartment, via the xc- transporter, reduce it intracellularly to cysteine and secrete surplus cysteine which can be readily taken up by neighboring cancer cells via the ubiquitous ASC transport system 1. This particular growth-promoting function of the stromal cells has been well established using co-cultures of fibroblasts and lymphoma cells which do not express a cystine transporter; the former acting as feeder layers supplying cysteine essential for growth of the lymphoma cells 1, 4. In view of this, inhibition of the xc- transporter leading to glutathione depletion has been proposed initially by us 2, 2a, and recently by others 11, as a potential therapeutic approach for a variety of cancers 1-11. Sulfasalazine, a relatively non-toxic FDA-approved drug, first discovered in our laboratory as a potent xc- inhibitor 5, has shown promise in arresting growth and reducing drug resistance of a variety of experimental lymphoid 4, 5, prostatic 7, 9, mammary 6 and pancreatic cancers 10.

In evaluating new therapeutic approaches, it is essential to use clinically relevant cancer models. I am very happy to be associated with the Living Tumor Laboratory which has developed cancer models that closely mimic malignancies as presented in the clinic 12-14.

 

References

1. Lo M, Wang YZ, Gout PW. The xc- cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases. J Cell Physiol 2008;215:593-602.

2. Gout PW, Kang YJ, Buckley DJ, Bruchovsky N, Buckley AR. Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells. Leukemia 1997;11:1329-1337. 2a: Gout PW. Progression of Nb2 lymphoma cells from hormonal dependency: association with increased cystine uptake via the xc- transport system. Proc 79th Ann Mtg Endocrine Soc (Minneapolis) 1997;#P3-16, p. 440.

3. Lo M, Ling V, Wang YZ, Gout PW. The xc- cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance. Br J Cancer 2008;99:464-472.

4. Gout PW, Simms CR, Robertson MC. In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine. Anticancer Drugs 2003;14:21-29.

5. Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc- cystine transporter: a new action for an old drug. Leukemia 2001;15:1633-1640.

6. Narang VS, Pauletti GM, Gout PW, Buckley DJ, Buckley AR. Sulfasalazine-induced reduction of glutathione levels in breast cancer cells: Enhancement of growth-inhibitory activity of doxorubicin. Chemotherapy 2007;53:210-217.

7. Doxsee DW, Gout PW*, Kurita T, Lo M, Buckley AR, Wang Y, Xue H, Karp CM, Cutz J-C, Cunha GR, Wang YZ. Sulfasalazine-induced cystine starvation: potential use for prostate cancer therapy. The Prostate 2007;67(2):162-171.

8. Guan J, Lo M, Dockery P, Mahon S, Karp CM, Buckley AR, Lam S, Gout PW, Wang YZ. The xc- cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: Use of sulfasalazine. Cancer Chemother Pharmacol 2009. 64 (3):463. Epub ahead of print.

9. Kagami T, Wang Y, Tien A, Watahiki A, Lo M, Xue H, Gout PW, Wang YZ. Sulfasalazine enhances growth-inhibitory activity of doxorubicin: Potential use in combination chemotherapy of advanced prostate cancer. Proc 98th Ann Mtg Am Assoc Cancer Res (Los Angeles, CA) 2007; Late-breaking Abstract #LB-322, p81.

10. Lo M, Wang YZ, Ling V, Gout PW. The xc- cystine transporter as a target for sensitizing pancreatic cancer to gemcitabine: Use of sulfasalazine. Proc 99th Ann Mtg Am Assoc Cancer Res (San Diego, CA) 2008; Abstract No. 2293.

11. Chung WJ, Lyons SA, Nelson GM, et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 2005;25:7101-10.

12. Cutz J-C, Guan J, Bayani J, Yoshimoto M, Xue H, Sutcliffe M, English J, Flint J, LeRiche J, Yee J, Squire JA, Gout PW, Lam S, Wang YZ. Establishment in severe combined immunodeficiency mice of subrenal capsule xenografts and transplantable tumor lines from a variety of primary human lung cancers: potential models for studying tumor progression-related changes. Clin Cancer Res 2006;12:4043-4054.

13. Wang Y, Xue H, Cutz J-C, Bayani J, Mawji N, Chen WG, Goetz L, Hayward SW, Sadar MD, Gilks CB, Gout PW, Squire JA, Cunha GR, Wang YZ. An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Lab Invest 2005;85(11):1392-1404.

14. Lee C-H, Xue H, Sutcliffe M, Gout PW, Huntsman DG, Miller DM, Gilks CB, Wang YZ. Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models. Gyn Oncol 2005;96(1):48-55. 

 

Publications

 

 

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