PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson NSAIDs in the Treatment and Prevention of Cancer Andrew Girgis, Cheng Yu Lin, Christopher Freige, Hassan Badreddine PHM142 Presentation 11-17-2015 What are NSAIDs? Non-Steroidal Anti-Inflammatory Drugs Uses Classification Mechanism of Action Salicylates Propionic Acid derivatives Acetic Acid derivatives Classification Selective COX-2 Inhibitors Enolic Acid derivatives Oldest and most commonly used drugs NSAIDs: History Ancient Greeks and Romans extracted salicylate from willow leaves for use as analgesics and antipyretics Salicylate from wintergreen and meadowsweet plants extracted during the middle ages Aspirin was first synthesized NSAID (acetylsalicylic acid – 1860) Not until 1970s was the mechanism of NSAIDs as an anti-inflammatory (inhibits prostaglandin) demonstrated COX-1 enzyme isolated in late 70s COX-2 enzyme identified in late 80s Selective COX-2 inhibitor (Celebrex and Vioxx) approved in late 90s NSAIDs and Inflammation Pathway NSAIDs (inhibit COX enzymes) • Almost 20% of human cancers are related to chronic inflammation • Cells and mediators of the innate immune system are detected in all cancers Cancer and Inflammation • Cyclooxygenase (COX)-2 enzymes have an important function in driving tumorigenesis through the production of prostaglandins • Accordingly, established agents that target COX-2 in the treatment of other diseases have been investigated for effectiveness as treatments of cancer. Vascular Angiogenesis PGE2 overexpression in Cancer VEGF IL-10 IL-12 Immune Suppression Metastasis Invasion MMP-2 MMP-9 PGE2 Reduced Apoptosis BCL-2 PI3-K Activation Proliferation Motility Dixon, D. (2015) NSAIDs have been shown to induce apoptosis in cancer cells. COX-2 over-production has been shown to increase in cancer cells NSAIDs and Cancer COX-2 inhibition by NSAIDs induces apoptosis in cancer cells There have also been studies to show that NSAIDs might have another target in cancer cells. Regular use of aspirin reduced the risk of CRC Aspirin and Colorectal Cancer In these observational studies, the regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis Aspirin reduced the risk of cancer development (324 vs 421) Frequent use of Aspirin significantly decreased mortality (562 vs 664) The adverse-effect profile of aspirin and NSAIDs can be substantial, including an increased risk of major bleeding. Cellular Studies COX-2 in Prevention of Cancer Overexpression of COX-2 in epithelial cells results in: Decreased apoptosis Angiogenesis (increased VEFG, FGF, PDGF… expression) Metastatic potential (increased adhesion and MMP expression) Epidemiological Studies Mice defective in COX-2 have a dramatic reduction (86%) in colorectal polyp formation. Long-term NSAID use is associated with reduced risk of developing cancer 32 996 participants Pooled analysis of 5 trials observed reduction in risk after 5 years followup among daily users of aspirin NSAIDs and Chemoprevention Rothwell, PM. (2012) Nitro-NSAIDs reduced GI toxicity Modified NSAIDs at therapeutic frontier Phosphotidylcholine (PC) NSAIDs eliminates GI toxicity Sulindac derivatives phospho-sulindac: > 10 fold more potent and efficacious than sulindac. Phospho-NSAIDs improved bioavailability Major Barriers to overcome GI toxicity: nausea, dyspepsia, and GI bleeding. Cardiovascular complications (except for aspirin): MI, heart failure, stroke A future of risk/benefit juggle Potential Solutions Combined Therapy Difluoromethylornithine (DFMO) and phospho sulindac greater GI safety and high potency at impairing cancer cell growth Aspirin: Heart healthy, but lower effect on carcinogenesis. Timing: high-risk groups to receive prophylactic NSAIDs at younger age. NSAIDs are classified based on their chemical structure or mechanism of action Aspirin is the first NSAID synthesized NSAIDs’ anti-inflammatory properties come from the inhibition of prostaglandin synthesis Summary COX-2 enzymes are important in driving tumorigenesis , and its inhibition by long-term NSAID use induces tumor cell apoptosis Adverse effects associated with NSAIDs can be attenuated via chemical modifications. Combination therapy using DMFO and modified NSAIDs showed strong anti-cancer effects while minimizing GI toxicity. Crusz, S., & Balkwill, F. (2015). Inflammation and cancer: Advances and new agents. Nature Reviews Clinical Oncology Nat Rev Clin Oncol, 12, 584-596. Frölich, J. (1997). A classification of NSAIDs according to the relative inhibition of cyclooxygenase isoenzymes. Trends in Pharmacological Sciences, (1), 30-34. References Rothwell, P., Price, J., Fowkes, F., Zanchetti, A., Roncaglioni, M., Tognoni, G., . . . Meade, T. (2012). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet, (1), 1602-1612. Samuelsson, B. (1991). Arachidonic acid metabolism: role in inflammation. Z Rheumatol, (1), 3-6 Tsioulias, G., Go, M., & Rigas, B. (2015). NSAIDs and Colorectal Cancer Control: Promise and Challenges. Curr Pharmacol Rep Current Pharmacology Reports, (1), 295-301.