NSAIDs in the Treatment and Prevention of CancerAndrew Girgis, Cheng Yu Lin, Christopher Freige, Hassan Badreddine PHM142 Presentation

11-17-2015

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

What are NSAIDs?

Non-Steroidal Anti-Inflammatory DrugsUsesClassificationMechanism of Action

Classification

Salicylates Propionic Acid derivativesAcetic Acid derivatives

Selective COX-2 Inhibitors Enolic Acid derivatives

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 and Inflammation Pathway

NSAIDs

(inhibit COX enzymes)

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.

PGE2 overexpression in Cancer

VascularAngiogenesis

ImmuneSuppression

ReducedApoptosis

ProliferationMotility

VEGF

PGE2

MetastasisInvasion

MMP-2 MMP-9 BCL-2

PI3-KActivation

IL-10 IL-12

Dixon, D. (2015)

NSAIDs and Cancer

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.

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.

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.

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

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

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, strokePotential 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.

Summary

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.

References

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.