NSAIDs in the Treatment and Prevention of Cancer 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 What are NSAIDs?

Classification Salicylates Propionic Acid derivatives Acetic Acid derivatives 3 classifications: Carboxylic acids, enolic acids, COX 2 inhibitors Acetasalicylic acid- Aspirin Ibuprofen- Advil Diclofenac- Voltaren Celecoxib- Celebrex Phenylbutazone-Bute- used in horses, no longer in use for humans Enolic Acid derivatives Selective COX-2 Inhibitors

NSAIDs: History Oldest and most commonly used drugs 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: History

NSAIDs and Inflammation Pathway (inhibit COX enzymes) Inflammation involves the formation of histamine, bradykinins, and the arachidonic acid pathway. House keeping: COX-1 promotes the production of the natural mucus lining that protects the inner stomach NSAIDs inhibit cyclooxygenase production thus stopping prostaglandin, thromboxane and prostacyclin production Describe role of those 3 things

Cancer and Inflammation Almost 20% of human cancers are related to chronic inflammation Cells and mediators of the innate immune system are detected in all cancers 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. Cancer and Inflammation Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid. AA is liberated from the membrane glycerophospholipids by phospholipases. 3 Major pathways convert AA into biologically active eicosanoids. Cyclooxygenase (COX) catalyses a key step in the formation of prostaglandins.

PGE2 overexpression in Cancer Metastasis Invasion Vascular Angiogenesis Reduced Apoptosis MMP-2  MMP-9  VEGF  BCL-2  PGE2 IL-10  IL-12  PI3-K Activation Immune Suppression 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 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. NSAIDs and Cancer

Aspirin and Colorectal Cancer Regular use of aspirin reduced the risk of CRC 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. Aspirin and Colorectal Cancer

COX-2 in Prevention of Cancer Cellular Studies 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. COX-2 in Prevention of Cancer

NSAIDs and Chemoprevention 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 Individual patient data for all fatal and non-fatal cancers were available from fi ve of the six trials of daily low- dose aspirin versus control in primary prevention (32 996 participants), 16–20 and for fatal cancers in the other trial 21 (2539 participants; appendix p 3). Pooled analysis of individual patient data showed that aspirin reduced risk of cancer during trial follow-up (hazard ratio [HR] 0·88, 95% CI 0·80–0·98, p=0·017; fi gure 2). No eff ect was noted during the fi rst 3 years of follow-up in the pooled analysis (fi gure 2), or in the individual trials, but benefi t became apparent with increasing follow-up thereafter (interaction with duration of follow-up, p=0·04; 0–2·9 years, HR 1·00, 95% CI 0·88–1·15, p=0·94; 3–4·9 years, HR 0·81, 95% CI 0·67–0·98, p=0·03; ≥5 years, HR 0·71, 95% CI 0·57–0·89, p=0·003). Overall benefi t was therefore most evident in patients with a scheduled duration of trial treatmen(ie, time of randomisation to end of trial) of 5 years or more (HR 0·81, 95% CI 0·70–0·93, p=0·003; fi gure 2). The reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66–0·88, p=0·0003) was independent of age, sex, and smoking status (table 3), but cancer deaths were only reduced from 5 years onwards (66 104 deaths; OR 0·63, 95% CI 0·47–0·86, p=0·004). In TPT, 16 which had a 2×2 factorial design, allocation to aspirin versus placebo reduced cancer incidence, but allocation to warfarin versus placebo did not (fi gure 3). The number of cancers in the six trials was too small to reliably establish eff ects of aspirin on specifi c cancer types. Combined analysis with data for fatal cancers from the other 26 trials in which primary site of cancers was known showed that risk of non-fatal or fatal cancer was reduced from 3 years onwards (407 514 cases; OR 0·79, 95% CI 0·70–0·90, p=0·0004; appendix p 4), the reduction being greatest for cancers of the female reproductive organs (34 63; OR 0·54, 95% CI 0·36–0·82, p=0·003), with trends towards fewer cancers of the uterus (zero nine; p=0·003, Fisher exact test), ovary (six 12; p=0·16), and breast (27 42; p=0·07). Across all of follow-up, there were also reductions in risks of lymphoma (25 45 cases; p=0·017) and sarcoma (one 11; p=0·007), but no signifi cant increase in incidence of any cancer. Rothwell, PM. (2012)

Modified NSAIDs at therapeutic frontier Nitro-NSAIDs reduced GI toxicity Phosphotidylcholine (PC) NSAIDs eliminates GI toxicity Sulindac derivatives phospho-sulindac: > 10 fold more potent and efficacious than sulindac. Phospho-NSAIDs improved bioavailability Modified NSAIDs at therapeutic frontier

A future of risk/benefit juggle Major Barriers to overcome GI toxicity: nausea, dyspepsia, and GI bleeding. Cardiovascular complications (except for aspirin): MI, heart failure, stroke 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. A future of risk/benefit juggle

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 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. Summary

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. 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. References