Amadeo Parissenti, PhD
Health Sciences North| Horizon Santé-Nord
41 Ramsey Lake Road
Sudbury ON Canada P3E 5J1
Phone: (705) 522-6237 ext. 2719
Fax: (705) 523-7326
|Professor, Division of Medical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario
Scientist, Research Program, Northeast Cancer Centre, Health Sciences North, 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
|Postdoctoral Research Fellowship in Medicine,
Banting and Best Department of Medical Research University of Toronto, Toronto, Ontario
|Postdoctoral Research Fellow in Medicine
Harvard Medical School & Joslin Diabetes Center, Boston, Massachusetts, USA
York University, Toronto, Ontario
University of Guelph, Guelph, Ontario
While chemotherapy drugs are highly effective in combating the growth of tumours, resistance to these drugs typically develops during treatment, resulting in treatment failure and progression of disease. Patients then move on to other chemotherapy drugs but these drugs often also become ineffective in halting tumour growth. This phenomenon is called “multidrug resistance”. The research efforts of my research group are focused on better understanding factors that affect the response of tumours to chemotherapy drugs and how tumour cells develop resistance to chemotherapy.
Role of Aldoketoreductases in Resistance to the Anthracycline Class of Chemotherapy Drugs
We have recently observed that breast tumour cells that have acquired resistance to a class of chemotherapy drugs called anthracyclines have high levels of protein molecules called aldo keto-reductases (AKRs). The AKRs play a natural role in breast cells, where they stimulate estrogen production. Estrogen, in turn, stimulates rapid growth of breast tumour cells, making them very sensitive to anthracyclines. To counteract this, we observed that anthracycline-resistant cells produce very little of the receptor for estrogen. The cells thus grow more slowly and are not killed effectively by chemotherapy drugs. In addition, the AKRs have the ability to alter the structure of anthracyclines, converting the drug to a form that can no longer reach its target in tumour cells (DNA within the nucleus). In fact, the drug appears to be sequestered in the lysosomes of cells away from the nucleus. Consequently, the altered drug is almost completely ineffective in killing breast tumour cells. It is also highly toxic to the heart. We have also shown recently that other drugs that inhibit the function of AKRs can prevent this change in anthraycline structure, restoring the ability of this class of drugs to kill tumour cells. In the future we plan to assess whether AKR-inhibitory drugs may improve the ability of anthracyclines to kill tumours in mice, while reducing damage to the heart.
Tumour Necrosis Factor Alpha and Response to the Taxane Class of Chemotherapy Drugs
Drugs such as paclitaxel and docetaxel (taxanes) are widely used in the treatment of a variety of human cancers, including breast and ovarian cancer. These drugs are known to bind to structures in normal and cancer cells called microtubules that play a role in separation of chromosomes between mother and daughter cells. This binding of the drug to microtubules prevents cell reproduction from taking place, particularly in rapidly proliferating cells such as tumour cells. This is thought to be the primary mechanism of action for taxanes. We have recently discovered that taxanes also promote in tumour cells a dramatic increase in the production and secretion of a death-inducing molecule called tumour necrosis factor alpha (TNFa). This may be a previously unknown mechanism by which taxanes kill tumour cells. Oddly, we have observed that breast tumour cells resistant to taxanes have even higher levels of TNFa. While this initially was puzzling, we also discovered that taxane-resistant cells are resistant to TNFa-induced killing because they have lost the receptor to which TNFa binds (TNFR1) in order to induce cell killing. In contrast, they have another receptor (TNFR2) to which TNFa can bind, which promotes tumour cell survival. Based on these novel findings, we now believe that TNFa plays an important role in tumour response and resistance to taxanes. We hope to be able to block this resistance mechanism in the future, in order to improve the effectiveness of taxane chemotherapy.
Guo, B., Reed, K. and Parissenti, A.M., (2006) Scanning mutagenesis studies reveal multiple distinct regions within human protein kinase C alpha regulatory domain important for Phorbol ester – dependent activation of 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., Hembruff, S.L., Guo, B.,Villeneuve, D.J., and Parissenti, A.M. (2007) Changes in Expression of Cell Wall Turnover Genes Accompany Inhibition of Chromosome Segregation by Bovine Protein Kinase C a 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., Guo, B., Villeneuve, D., Shuart, M., Cecchetto, M., and Parissenti, A.M. (2008) “Drug Transporters, Drug Accumulation Defects and the Temporal Acquisition of Resistance to Anthracyclines and Taxanes in MCF-7 Breast Tumour cells”. 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., Guo, B., 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, B., Han, L., O’Brien, P., Clemons, M. P., Jong, R., Dent, R., Fitzgerald, B., Pritchard, K. I., Shepherd, L. E., and Trudeau, M. E. (2010) Association of low tumour RNA integrity with response to chemotherapy in breast cancer patients. Breast Cancer Research and Treatment 2, 347-56.
Reed, K., Poulin, M. L., Yan, L. and Parissenti, A. M. (2010) Comparison of bisulfite sequencing PCR with pyrosequencing for measuring differences in DNA methylation. Analytical Biochemistry 1, 96-106.
Reed, K., Hembruff, S. L., Sprowl, J. A. and Parissenti, A. M. (2010) The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression, and the acquisition of drug resistance. The Pharmacogenomics Journal (E publication ahead of print).
Reed, K. and Parissenti, A. (2010) Epigenetic Regulation of ABCB1 Transporter Expression and Function. Current Pharmacogenomics and Personalized Medicine, in press.
Links to Website
|Regional Cancer Program, Sudbury Regional Hospital – Dr. Parissenti|