Current position(s)
Director of Research, Regional Cancer Program of the Hôpital Régional de Sudbury Regional Hospital, Sudbury, Ontario
Past Chair in Cancer Research, Regional Cancer Program of the Hôpital Régional de Sudbury Regional Hospital, Sudbury, Ontario
Professor, Division of Medical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario
Professor, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario
Assistant Professor, Department of Medicine, Division of Oncology, University of Ottawa, Ottawa, Ontario
Assistant Professor, Department of Biochemistry, Molecular Biology and Immunology, University of Ottawa, Ottawa, Ontario
Education and Training
1991-1995 Postdoctoral Research Fellowship in Medicine, Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario.
1989-1991 Postdoctoral Research Fellow in Medicine, Harvard Medical School & Joslin Diabetes Center, Boston, Massachusetts, USA
1989 Ph.D. York University (Biochemistry), Toronto, Ontario
1983 B.Sc. University of Guelph (Biochemistry), Guelph, Ontario
Awards and Honours
2008
Ontario Partnership for Innovation in Commercialization - OPIC Value: $10,000
Proposal “Method of Using RNA Integrity to Measure Patient Response to Chemotherapy”
2002
Government of Ontario, Premier’s Research Excellence Award, Value: $150,000
Research Funding
Canadian Institutes of Health Research (CIHR)
Ontario Cancer Research Network (OCRN)
Pfizer Canada Inc.
Xanthus Pharmaceuticals
YM Biosciences Inc.
Canada Foundation for Innovation
Ministry of Science and Technology
R. Samuel McLaughlin Foundation
Ontario Research and Development Challenge Fund
Canadian Breast Cancer Foundation
Cancer Care Ontario
Northern Cancer Research Foundation
Sudbury Regional Hospital Foundation
Medical Research Council of Canada
Research Investigations
Mechanisms, Detection, and Reversal of Resistance to Anthracyclines and Taxanes in Human Breast Cancer
We have established a panel of isogenic cell lines that have been selected for resistance to increasing concentrations of chemotherapy drugs used in the treatment of human breast cancer. Since the cell lines all originate from the same source and were selected in an identical manner, they should be invaluable in examining the mechanisms by which tumour cells are able to resist the killing action of chemotherapy agents. Since the phenomenon of drug resistance was first discovered in the late 1970s, much of the research in this field has focused on the role of drug transporters, which have been found to be overexpressed in drug-resistant tumour cells, where they increase the ability of tumour cells to excrete chemotherapy drugs. Recently, we found that as breast tumour cells are exposed to increasing concentrations of two classes of chemotherapy drugs (anthracyclines and taxanes), resistance is acquired at a precise "threshold" concentration. Interestingly, while the expression of specific drug transporters is increased above the threshold concentration, so are a number of additional gene products, including a very strong induction of the 1C family of aldoketoreductases. These enzymes can convert anthracyclines to less cytotoxic 13-hydroxy metabolites and may also block DNA damage by anthracyclines by blocking the generation of reactive oxygen species (ROS). Interestingly, broad spectrum inhibition of drug transporters in drug-resistant cells could significantly or fully restore drug uptake into cells, but this resulted in partial or no increase in drug sensitivity. In contrast, inhibition of the 1C family of aldoketoreductases almost completely restored sensitivity to doxorubicin in doxorubicin-resistant cells. We are currently assessing whether the generation of 13-hydroxy metabolites or the inhibition of ROS represents the primary mechanism(s) by which aldoketoreductases confer resistance to anthracyclines. If so, then inhibition of aldoketoreductases may represent a new approach to reverse drug resistance in tumour cells (alone or in concert with drug transporter inhibitors). In additional studies, we have uncovered a strong relationship between the cytotoxicity of the taxane docetaxel and the ability of this drug to induce tumor necrosis factor alpha. We also show that tumor necrosis factor alpha signaling pathways are dramatically altered upon selection of breast tumour cells for resistance to We are examining in partnership with the National Cancer Institute of Canada Clinical Trials group whether any of these newly identified pathways to drug resistance in vitro have relevance to clinical drug resistance in breast cancer patients.
Protein Kinase C: Structure/Function Relationships and Role in Cellular Growth Control
We have recently published evidence that the activity of the protein kinase C alpha (PKC alpha) catalytic domain can be potently and specifically inhibited by its regulatory (R) domain without requiring the "pseudosubstrate" site within the PKC R domain. Pseudosubstrates strongly resemble enzyme substrates, but lack a phosphorylatable amino acid, thereby blocking enzyme activity. Since there are no additional pseudosubstrate like sites within this R domain, this observation challenges the currently predominant role of pseudosubstrates in the autoinhibition of protein kinases and suggests that additional site(s) are involved. Through deletion mutagenesis studies, we have now established that one inhibitory region lies between amino acids 36-177. Since this region lacks the PKC, Ca++ and phosphatidylserine binding sites, and since inhibition can occur in a phorbol ester-independent manner, it appears that the mechanism does not involve sequestration of PKC activators/cofactors. Possible inhibition of PKC catalytic activity by binding the PKC substrate used in our assays has also been ruled out. The additional sites within the PKC R domain contributing to PKC autoinhibition are being more finely localized by alanine linker-scanning and site directed mutagenesis approaches. We have also observed that expression of mammalian PKC alpha in yeast results in potent inhibition of cell growth. Growth repression is accompanied by changes in the expression of genes involved in cell wall turnover and a defect in chromosome segregation. We are currently elucidating the precise mechanism by which PKC inhibits cell growth, including possibly direct or indirect changes in the phosphorylation of the cdc55 phosphatase and the activity of the Ace2 transcription factor.
Selected publications
Guo, B., Villeneuve, D. J., Kirwan, A. F., Hembruff, S. L., Blais, D. E., Bonin, M. and Parissenti, A. M. (2004) Cross resistance studies of isogenic drug-resistant breast tumour cell lines support clinical evidence suggesting that sensitivity to paclitaxel may be strongly compromised by prior doxorubicin exposure. Breast Cancer Res. Treat. 85:31-51.
Bewick, M., Conlon, M., Lee, H., Parissenti, A.M., Zhang, L., Gluck, S., Lafrenie, R.M. (2004) Evaluation of sICAM-1, sVCAM-1, and sE-Selectin Levels in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy. Stem Cells Dev. 3:281-94.
Parissenti, A.M. and Villeneuve, D.J. (2004). Invited Review: The Use of DNA microarrays to investigate the Pharmacogenomics of Drug Response in Living Systems. Current Topics in Medicinal Chemistry 4:1329-1345.
Hembruff, S.L., Villeneuve, D.J. and Parissenti, A.M. (2005) The Optimization of quantitative reverse transcription PCR for verification of cDNA microarray data. Analytical Biochemistry 345, 237-249.
Kumar, A., Kumar, A., Michael, P., Brabant, D., Parissenti, A.M., Ramana, C.V., Xu, X., and Parrillo, J.E. (2005) Human Serum from Patients with Septic Shock Activates Transcription Factors Stat1, IRF1 and NF-kB and induces apoptosis in human cardiac myocytes. Journal of Biological Chemistry 280, 42619-42626.
Villeneuve, D.J., Hembruff, S.L., Veitch, Z., Cecchetto, M., Dew, W.A., and Parissenti, A.M. (2006) cDNA Microarray Analysis of Isogenic Paclitaxel- and Doxorubicin-Resistant Breast Tumor Cell Lines Reveals Distinct Drug-Specific Genetic Signatures of Resistance. Breast Cancer Research and Treatment 96, 17-39.
Guo, B., Reed, K. and Parissenti, A.M. (2006) Scanning mutagenesis studies reveal multiple distinct regions within the human protein kinase C alpha regulatory domain important for phorbol ester-dependent activation of the enzyme”. Journal of Molecular Biology 357, 820-832.
Parissenti, A.M., Hembruff, S.L., Villeneuve, D.J., Veitch, Z., Guo, B., Eng, J. (2007) Invited Review: Gene expression profiles as biomarkers for the prediction of chemotherapy drug response in human tumour cells. Anti-Cancer Drugs 18, 499-523.
Sprowl, J., Villeneuve, D.J., Guo, B., Young, A.J., Hembruff, S.L., and Parissenti, A.M. (2007) Changes in expression of cell wall turnover genes accompany inhibition of chromosome segregation by bovine protein kinase C alpha expression in Saccharomyces cerevisiae. Cell Biol Int 31, 1160-1172.
Reed, K., Hembruff, S.L., Laberge, M.L., Villeneuve, D.J., Côté, G.B., and Parissenti, A.M. (2008) Hypermethylation of the ABCB1 downstream gene promoter accompanies ABCB1 gene amplification and increased expression in docetaxel-resistant MCF-7 breast tumor cells. Epigenetics, 3(5), 270-280.
Hembruff, S.L., Laberge, M., Veitch, Z., Villeneuve, D., Shuart, M., Cecchetto, M., and Parissenti, A.M. (2008) Role of Drug Transporters and Drug Accumulation in the Temporal Acquisition of Drug Resistance. BMC Cancer 8, 318.
Hussein, S., Michael, P., Brabant, D., Omri, A., Narain, R., Passi, K., R. V. Chilakamarti., Parrillo, J.E., Kumar, A., Parissenti, A.M., and Kumar, A. (2009) Characterization of Human Septic Sera Induced Gene Expression Modulation in Human Myocytes. Int. J. Clin Exp Med. 2, 131-148.
Veitch, Z., Hembruff, S.L., Eng, J.R., MacLean, D.A., Heibein, A.D., Bewick, A., Cull, S., and Parissenti, A.M. (2009) Induction of Aldoketoreductases IC2 and IC3 and other Drug Dose-dependent Genes Upon Acquisition of Anthracycline Resistance. Pharmacogenetics and Genomics 6, 477-488.
Parissenti, A. M., Chapman, J.W., Kahn, H. J., Guo, G., Han, L., O’Brien, P., Clemons, M. P., Jong, R., Dent, R., Fitzgerald, B., Pritchard, K. I., Shepherd, L. E., and Trudeau, M. E. (2009) Association of low tumour RNA integrity with response to chemotherapy in breast cancer patients. In Press: Breast Cancer Research and Treatment.
Reed, K., Hembruff, S. L., Sprowl, J. A. and Parissenti, A. M. (2009) The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression, and the acquisition of drug resistance. The Pharmacogenomics Journal, accepted pending revisions.
Reed, K., Poulin, M. L., Yan, L. and Parissenti, A. M. (2009) Comparison of the efficiency of bisulfite sequencing PCR and pyrosequencing to measure hypomethylation, hypermethylation, and mixed methylation of DNA. Analytical Biochemistry, accepted pending minor revisions.
Book Chapters