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Prostate Cancer and Cytotoxic Treatment Found in the Sea Anemone, Stichodactyla helianthus By: Diem Nguyen, Rachel Jones and David Waid University of New.

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Presentation on theme: "Prostate Cancer and Cytotoxic Treatment Found in the Sea Anemone, Stichodactyla helianthus By: Diem Nguyen, Rachel Jones and David Waid University of New."— Presentation transcript:

1 Prostate Cancer and Cytotoxic Treatment Found in the Sea Anemone, Stichodactyla helianthus By: Diem Nguyen, Rachel Jones and David Waid University of New Mexico Department of Biology Spring 2012

2 Introduction History of Prostate Cancer: Leading cause of illness and death among men in the United States and Western Europe 2011: An estimated 240,900 men were diagnosed with prostate cancer 33,720 deaths

3 Underlying causes of disease ~ 42% caused by genetic influences Mutations Genetic instability Heritable traits, etc. ~ 58% caused by environmental factors Diet Lifestyle Carcinogens Inflammation, etc.

4 Conventional Treatments Traditional Chemotherapy Radical prostatectomy Direct implantation of radioactive seeds into the prostate Castration via surgical and hormonal methods

5 Prospective Clinical Trials Immunotoxin Chemotherapy on cancer cells Shown to be effective in eliminating tumor growth Mice, adult Hodgkin's and non-Hodgkin's lymphoma, pediatric lymphocytic leukemia Fact: Traditional Immunotoxins require internalization and translocation into the cell in order to enact a cytotoxic effect Problem: This could induce other cellular responses Excessive destruction of healthy cells Degradation of lysosomes Solution: “Stay tuned…”

6 What are Immunotoxins (ITs)? Synthesized, chimeric molecules Cytotoxic agent + monoclonal antibody Targets tumorous lesions Cytotoxic and lytic effects on cancer cells Primary Candidate: Sticholysin I (StI) a cytolysin found in the sea anemone, Stichodactyla helianthus may be a beneficial immunotoxin for the cytolytic destruction of prostate tumor cells

7 Sticholysin I (StI) A pore-forming toxin (actinoporin) Induce cellular lysis via contact with plasma membrane, causing lethal pore development Able to irreversibly bind and interact with cell membranes Tryptophan rich region at N-terminus of toxin acts as the binding site to anchor itself to the plasma membrane, promoting pore-formation

8 Proposal for Cytotoxic Chemotherapy Treatment Recall… Fact: Traditional Immunotoxins require internalization and translocation into the cell in order to enact a cytotoxic effect Problem: This could induce other cellular responses Excessive destruction of healthy cells Degradation of lysosomes Proposed Solution: Provide a modified cytolysin, Sticholysin I (StI), enabling it to bind more selectively to tumor cells, inducing cytotoxic activity on prostate cancer cells.

9 Mechanism of Action Step 1: Block tryptophan binding site of N-terminus by introduction of cysteine residues providing a peptide link between StI and a avidin molecule. The avidin, and cysteine residue complex will render tryptophan binding site inactive. New cytotoxin complex will bind to the cell membranes of prostate cells Avidin molecule Cysteine residues StI

10 Mechanism of Action (Cont.) Step 2: Insertion of newly synthesized cytotoxic agents into tumor via trans-rectal ultrasound (TRUS). a prostate tumor-secreted protease (i.e. matrix metalloproteinases) will cleave Cys-Cys peptide bond Avidin complex will release from StI, revealing tryptophan binding region Cleaving of cysteine complex from StI will reactivate the pore-forming cytotoxin Exposure of binding region will allow it to anchor itself on the plasma membrane and bore holes in cancerous cells This will induce pore-forming activity of tryptophan on tumor cells within the vicinity of the agent Colloidal osmotic shock will ensue, resulting in the apoptosis of the cells

11 Results Studies have demonstrated that advanced prostate cancer frequently involves bone metastases. Our research has shown that pore-forming cytotoxins may be effective in inhibiting tumor proliferation, thereby, serving as an viable anti-cancer treatment, while concurrently providing anti-metastasis tactics. Additionally, side effects and excessive destruction of healthy cells are minimized as the treatment is only effective within a certain radius of action.

12 Implications of Treatment Predict that greatest therapeutic benefit of treatment will be in individuals with early onset prostate cancer This may be attributed to a more rapid upregulation of cellular processes upon exposure to cytotoxin Effective filter mechanisms with selected phenotypes either decreases later in life or cancer processes adapt to circumvent defenses Due to cancerous cells rapidly proliferating and disseminating, they may eventually acclimate to immunotoxic treatments

13 Limitations of Research Lack of specificity of avidin ligand may cause lysis of normal cells prior to reaching target tumor Possible solution: Attach an antibody to the avidin end of ligand to further increase specificity Cytolysin has dependence on sphingomyelin levels in order to initiate interaction with cellular membranes.

14 Discussion Reducing Side Effects Pore-forming cytotoxins are highly potent and lyse most cells Further trials should be conducted to determine safe amounts for administration Careful titration of immunotoxin must be observed by MRI and other imaging technology

15 Discussion Cont. Influences on to consider for Prostate Cancer: Diet High levels protein has been shown to be a potent carcinogenic factor Carcinogens; air pollutants, environmental chemicals Lifestyle choices (i.e. smoking, inactivity) Genetic predispositions

16 Future Research Produce an immunotoxin with specificity that targets only cancerous cells via attachment of antibody to avidin end of ligand Allow for recognition of tumor cell surface antigen Provide immunotoxin treatment to individuals with a restricted protein intake Examine efficacy of diet and therapy versus therapy alone We hypothesize that a greater therapeutic benefit would be observed in patients with low protein consumption and concurrent treatment

17 Literature Cited  Nelson, W., De Marzo, A., Isaacs, W. 2003. Mechanisms of disease: Prostate cancer. New England Journal of Medicine. 349: 366-381.  Denmeade, S. & Isaacs, J. 2002. A history of prostate cancer treatment. Nature Publishing Group. 2: 389-396.  Alvarez, C., Macheno, J., Martinez, D., Tejuca, M., Pazos, F., and Lanio, M. 2009. Sticholysins, two pore-forming toxins produced by the Caribbean Sea anemone Stichodactyla helianthus: Their interaction with membranes. Toxicon. 2009. 54: 1135-1147.  Tejuca, M., Anderluh, G., and Dalla Serra, M. 2009. Sea anemone cytolysins as toxic components of immunotoxins. Toxicon. 54: 1206-1214.  Estevez-Calvar, N., Romero, A., Figueras, A., and Novoa, B. 2011. Involvement of pore-forming molecules in immune defense and development of the Mediterranean mussel (Mytilus galloprovincialis). Developmental and Comparative Immunology. 35:1015-1029.  Anderluh, G. & Menestrina, G. 2001. Pore-forming proteins from sea anemones and the construction of immunotoxins for selective killing of harmful cells in bio-organic compounds: chemistry and biochemical applications. Science Publishers, Inc. 131-148.  Bok, R., Hansell, E., Nguyen, T., Greenberg, N., McKerrow, J., and Shuman, M. 2003. Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model. Prostate Cancer and Prostatic Diseases. 6: 272-280.  Theodorescu, D., Krupski, T., Rukstalis, D., Francisco, T., and Kim, E. 2011. Prostate cancer - brachytherapy (radioactive seed implantation therapy). http://emedicine.medscape.com/article/453349- overview#aw2aab6b3 http://emedicine.medscape.com/article/453349- overview#aw2aab6b3  Campbell. T. C. & Campbell, T. M. 2006. The China study: Startling implication for diet, weight loss, and long-term health. 43-68.


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