NSAIDS in the Treatment and Prevention of Cancer

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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.
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