1. NSAIDs in the Treatment and Prevention of Cancer
PHM 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

2. What are NSAIDs? Non-Steroidal Anti-Inflammatory Drugs Uses
Classification
Mechanism of Action
What are NSAIDs?

3. 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

4. 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

5. 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

6. 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.

7. 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)

8. 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

9. 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

10. 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

11. NSAIDs and Chemoprevention
Long-term NSAID use is associated with reduced risk of developing cancer
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
( 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)

12. 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

13. 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

14. 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

15. Crusz, S., & Balkwill, F. (2015). Inflammation and cancer: Advances and new agents. Nature Reviews Clinical Oncology Nat Rev Clin Oncol, 12,
Frölich, J. (1997). A classification of NSAIDs according to the relative inhibition of cyclooxygenase isoenzymes. Trends in Pharmacological Sciences, (1),
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),
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),
References