Ibuprofen
Multi-species lifespan extension (2014):
Yeast: 17% increase in replicative lifespan with 0.2 mM ibuprofe.
Nematodes (C. elegans): 12% increase in mean lifespan with 0.1 mM ibuprofen.
Fruit flies (D. melanogaster): 17% increase in mean lifespan for females with 0.5 μM ibuprofen.
Suggests a conserved pro-longevity mechanism across evolutionarily divergent species.
Protective associations against multiple cancer types (2024 umbrella review):
Overall NSAID use associated with reduced risk in 8 cancer types.
Aspirin use associated with reduced risk in 12 cancer types.
Non-aspirin NSAID use (including ibuprofen) associated with reduced risk in 5 cancer types.
Cancer prevention may contribute to increased lifespan.
Anti-inflammatory and pro-resolving effects (2022):
Ibuprofen modulates inflammatory pathways and promotes resolution of inflammation.
Chronic inflammation is associated with accelerated aging and age-related diseases.
By reducing inflammation, ibuprofen may slow the aging process.
Potential neuroprotective effects (2009):
Previous research suggested protective effects against age-related neurodegenerative diseases like Alzheimer's and Parkinson's.
Preservation of cognitive function could contribute to increased healthspan and lifespan.
Cell cycle modulation (2014):
0.2 mM ibuprofen reduced cell size at birth by ~10% and moderately delayed G1 phase in yeast.
Similar cell cycle patterns were observed in long-lived yeast mutants.
These changes may promote cellular health and longevity.
Anti-cancer effects (2022):
Ibuprofen diminished cancer cell stemness properties in vitro.
Reduced ALDH+ subpopulations by 50-75% in breast, lung, and liver cancer cell lines.
Inhibited tumor growth by ~65% and increased median survival from 36 to 46 days in mouse models.
May reduce cancer risk and improve survival in humans.
Inhibition of tryptophan import (2014):
In yeast, ibuprofen reduced intracellular levels of aromatic amino acids by 15-20%.
Decreased tryptophan levels may trigger mild stress responses that promote longevity.
Similar mechanisms might exist in higher organisms.
Epigenetic modifications (2022):
Increased histone 3 methylation and acetylation markers by 1.5-3 fold.
Decreased expression of histone demethylases by 50-70%.
These changes may promote healthier gene expression patterns associated with longevity.
NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase (2022)
Key Findings:
Ibuprofen diminishes cancer cell stemness properties in vitro:
Reduced ALDH+ subpopulation, side population, and sphere formation in breast cancer (MDA-MB-231), lung cancer (A549), and liver cancer (HepG2) cell lines.
At 0.5 mM and 1 mM ibuprofen concentrations, ALDH+ populations decreased by approximately 50-75% compared to controls across the three cancer types.
Side populations were reduced by about 40-60% with ibuprofen treatment.
Sphere formation was inhibited by roughly 50-70% in ibuprofen-treated cells.
Ibuprofen inhibits tumor growth, metastasis, and prolongs survival in vivo:
In a 4T1-luciferase breast cancer mouse model, 20 mg/kg and 40 mg/kg ibuprofen treatment reduced tumor volume by ~50% and ~65% respectively after 30 days.
Lung metastasis was decreased by ~60% with 20 mg/kg ibuprofen and ~80% with 40 mg/kg.
Median survival increased from 36 days in controls to 43 days with 20 mg/kg ibuprofen and 46 days with 40 mg/kg.
Ibuprofen reduces cancer cell chemoresistance in vivo:
In mice treated with cisplatin + ibuprofen, tumor volume was reduced by ~40% (10 mg/kg ibuprofen) and ~60% (20 mg/kg ibuprofen) compared to cisplatin alone.
Median survival increased from 38 days (cisplatin alone) to 45 days (cisplatin + 10 mg/kg ibuprofen) and 49 days (cisplatin + 20 mg/kg ibuprofen).
Ibuprofen inhibits expression of inflammation-related stemness genes:
Decreased protein and mRNA expression of ICAM3, CCL16, PDE3A, PRTN3, TRAF6, BCAR1, IL-1α, IL-1β, NFκB1, IκBκB, SOX2 and OCT4 in vitro and in vivo.
ICAM3 protein levels were reduced by ~50-70% across the three cancer cell lines.
Ibuprofen mediates histone modifications to affect gene expression:
Increased expression of histone 3 trimethylation markers (H3K4-3Me, H3K9-3Me, H3K27-3Me, H3K36-3Me, H3K79-3Me) by 1.5-3 fold.
Decreased expression of histone demethylases KDM6A and KDM6B by ~50-70%.
Increased histone 3 acetylation markers (H3K18-Ac, H3K27-Ac) by 2-3 fold.
Reduced expression of HDACs 1-5 by ~40-60%.
Decreased HDAC activity by ~50% in ibuprofen-treated cells.
Ibuprofen's effects are COX2-dependent:
Knocking down COX2 partially rescued the decrease in ALDH+ and side populations caused by ibuprofen (by ~30-50%).
COX2 knockdown also partially reversed ibuprofen's effects on histone modifications and ICAM3 expression.
Combination therapy with ibuprofen and epigenetic inhibitors shows promise:
In an A549 lung cancer mouse model, combining ibuprofen (20 mg/kg) with HDAC inhibitor TSA (0.5 mg/kg) and KDM6A/B inhibitor GSK J1 (100 mg/kg) reduced tumor volume by ~75% compared to controls after 30 days.
Median survival increased from 46 days (control) to 68 days with the combination therapy.
Conclusions:
Ibuprofen exhibits anti-cancer stem cell properties across multiple cancer types (breast, lung, liver) by reducing stemness markers, sphere formation ability, and chemoresistance both in vitro and in vivo.
The mechanism of action involves epigenetic modifications, particularly increased histone 3 methylation and acetylation, leading to suppressed expression of inflammation-related stemness genes like ICAM3.
Ibuprofen's effects are largely dependent on COX2 expression, suggesting both COX-dependent and COX-independent mechanisms contribute to its anti-cancer properties.
Combining ibuprofen with epigenetic modifying drugs (HDAC and KDM inhibitors) shows enhanced anti-tumor effects, suggesting a potential new therapeutic strategy.
The relationship between nonsteroidal anti-inflammatory drugs and cancer incidence: An umbrella review (2024)
Key Points:
This umbrella review analyzed 80 meta-analyses examining the associations between NSAID use and cancer incidence for 20 unique cancer outcomes.
The review looked at three categories of NSAID exposure: overall NSAID use, aspirin use specifically, and non-aspirin NSAID (NA-NSAID) use.
For overall NSAID use, significant protective associations were found for 8 cancer types: breast, central nervous system (CNS), esophageal, gastric, head and neck, liver, prostate, and skin cancers.
For aspirin use specifically, significant protective associations were found for 12 cancer types: breast, cholangiocarcinoma, colorectal, endometrial, esophageal, gastric, liver, lung, ovarian, prostate, pancreatic, and overall digestive system cancers.
For NA-NSAID use, significant protective associations were found for 5 cancer types: CNS, colorectal, esophageal, gastric, and skin cancers. However, NA-NSAID use was associated with an increased risk of kidney cancer.
Several dose-response relationships were identified, showing greater cancer risk reduction with higher NSAID doses or longer durations of use for some cancer types.
The review highlights multiple potential mechanisms by which NSAIDs may exert anti-cancer effects, including inhibition of cyclooxygenase (COX) enzymes, modulation of inflammatory pathways, and effects on cell signaling.
Despite the protective associations found, the authors caution that most included studies were evaluated as low quality evidence. They do not recommend regular NSAID use solely for cancer prevention due to potential side effects.
Detailed Results:
Overall NSAID Use:
Breast cancer: 12% reduced risk (RR 0.88, 95% CI 0.84-0.93)
CNS cancer: 11% reduced risk (RR 0.89, 95% CI 0.81-0.95)
Esophageal cancer: 42% reduced risk (OR 0.58, 95% CI 0.47-0.72)
Gastric cancer: 24% reduced risk (RR 0.76, 95% CI 0.70-0.82)
Head and neck cancer: 16% reduced risk (RR 0.84, 95% CI 0.76-0.93)
Liver cancer: 19% reduced risk (HR 0.81, 95% CI 0.69-0.94)
Prostate cancer: 11% reduced risk (RR 0.89, 95% CI 0.81-0.98)
Skin cancer: 18% reduced risk (RR 0.82, 95% CI 0.71-0.94)
Dose-response relationships:
CNS cancer: 5% risk reduction per 100 defined daily doses (RR 0.95, 95% CI 0.92-0.98)
CNS cancer: 6% risk reduction per 2 years of use (RR 0.94, 95% CI 0.92-0.98)
Head and neck cancer: 4% risk reduction per 2 prescriptions/week (RR 0.96, 95% CI 0.94-0.99)
Aspirin Use:
Breast cancer: 6% reduced risk (RR 0.94, 95% CI 0.91-0.97)
Cholangiocarcinoma: 44% reduced risk (OR 0.56, 95% CI 0.32-0.96)
Colorectal cancer: 26% reduced risk (RR 0.74, 95% CI 0.64-0.83)
Endometrial cancer: 7% reduced risk (RR 0.93, 95% CI 0.88-0.99)
Esophageal cancer: 33% reduced risk (OR 0.671, 95% CI 0.526-0.856)
Gastric cancer: 36% reduced risk (OR 0.64, 95% CI 0.54-0.76)
Liver cancer: 46% reduced risk (OR 0.54, 95% CI 0.44-0.66)
Lung cancer: 13% reduced risk (RR 0.87, 95% CI 0.79-0.95)
Ovarian cancer: 11% reduced risk (RR 0.89, 95% CI 0.83-0.96)
Prostate cancer: 7% reduced risk (RR 0.93, 95% CI 0.89-0.96)
Pancreatic cancer: 22% reduced risk (RR 0.78, 95% CI 0.68-0.89)
Overall digestive system cancer: 27% reduced risk (RR 0.73, 95% CI 0.69-0.78)
Dose-response relationships:
Colorectal cancer: 10% risk reduction per 75 mg/day increase
Colorectal cancer: 18% risk reduction at 7 times/week use vs. twice/week use
Colorectal cancer: 33% risk reduction at 20 years use vs. 5 years use
Endometrial cancer: 3% risk reduction at twice/week use
NA-NSAID Use:
CNS cancer: 14% reduced risk (RR 0.86, 95% CI 0.78-0.94)
Colorectal cancer: 26% reduced risk (OR 0.74, 95% CI 0.67-0.81)
Esophageal cancer: 45% reduced risk (OR 0.55, 95% CI 0.42-0.72)
Gastric cancer: 19% reduced risk (RR 0.81, 95% CI 0.74-0.90)
Skin cancer: 15% reduced risk (RR 0.85, 95% CI 0.78-0.94)
Kidney cancer: 25% increased risk (RR 1.25, 95% CI 1.06-1.46)
Dose-response relationships:
CNS cancer: 7% risk reduction per 3 prescriptions
CNS cancer: 8% risk reduction per 2 years of use
Conclusions:
NSAIDs, particularly aspirin, appear to have protective associations against multiple cancer types. However, the authors emphasize that most evidence was low quality.
Potential mechanisms for NSAID anti-cancer effects include:
Inhibition of COX enzymes and prostaglandin synthesis
Modulation of inflammatory pathways (e.g. NF-κB)
Effects on cell signaling pathways (e.g. Akt, MAPK)
Inhibition of angiogenesis
Regulation of the tumor microenvironment
Despite protective associations, the authors do not recommend regular NSAID use solely for cancer prevention due to potential side effects like gastrointestinal bleeding, ulcers, and cardiovascular risks.
More high-quality prospective studies are needed to better understand the relationships between NSAID use and cancer outcomes, including research on genetic polymorphisms and novel NSAID formulations.
The review has several limitations:
Few randomized controlled trials were included
Heterogeneity in how NSAID use was defined across studies
Potential confounding factors not fully accounted for
Focus only on published meta-analyses may have led to incomplete results
The authors conclude it is premature to recommend regular NSAID use for cancer prevention in the general population. Individualized assessment of risks and benefits is needed.
This umbrella review provides a comprehensive overview of the current evidence on NSAIDs and cancer risk, but highlights the need for further high-quality research to inform clinical recommendations.
In summary, this extensive umbrella review by Wang et al. (2024) synthesizes a large body of evidence on the potential cancer-preventive effects of NSAIDs. While protective associations were found for multiple cancer types, especially with aspirin use, the authors emphasize caution in interpreting these results due to the overall low quality of evidence. The review elucidates potential biological mechanisms for NSAID anti-cancer effects and identifies key areas for future research. However, given the potential side effects of NSAIDs, the authors do not recommend their use solely for cancer prevention without individual assessment of risks and benefits. This review provides an important foundation for understanding the complex relationships between NSAID use and cancer risk, while highlighting the need for more rigorous studies to inform clinical practice.
Ibuprofen in the Prevention and Therapy of Cancer (2015)
This chapter provides compelling evidence that regular intake of inexpensive and readily available non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, and that non-selectively block cyclooxygenase-2 (COX-2), protects against the development of many types of cancer. It synthesizes and interprets a series of progressive investigations of ibuprofen in human cancer prevention and therapy. The investigations presented here focus specifically on cancers of the colon, breast, prostate and lung. Results of meta-analyses of NSAIDs (primarily aspirin and ibuprofen) and cancer are included for comparison. Findings are generalized, molecular mechanisms of carcinogenesis reviewed and future perspectives are discussed on the exciting possibilities for COX-2 blockade by ibuprofen and related compounds in cancer prevention and therapy. The chapter demonstrates that ibuprofen and, to a lesser extent, aspirin, taken at low dosages for more than five years, have significant chemopreventive effects against a variety of malignant neoplasms.
NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase (2022)
The review article delves into the intricate relationship between inflammation and cancer, emphasizing the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancer resolution. The authors explore the mechanisms beyond cyclooxygenase (COX) inhibition that contribute to the anticancer effects of NSAIDs.
The article begins by tracing the historical understanding of inflammation, from its recognition as a healing process by Hippocrates to the link between inflammation and cancer proposed by Rudolf Virchow. The authors distinguish between acute inflammation, which is self-limiting and promotes homeostasis, and chronic inflammation, which can lead to various diseases, including cancer. The key features of cancer-related inflammation are highlighted, including the infiltration of white blood cells, tumor-associated macrophages, cytokines, and the acceleration of cell proliferation and angiogenesis. The evidence linking inflammation and cancer is strengthened by the observation that NSAIDs, particularly aspirin, reduce the risk and mortality from several cancers.
The authors then discuss the mechanism of action of aspirin, the only NSAID that irreversibly modifies COX enzymes. Aspirin acetylates both COX-1 and COX-2, leading to the inhibition of prostaglandin synthesis. The acetylation of COX-1 in platelets results in decreased thromboxane production, contributing to aspirin's antithrombotic properties and potential for cardiovascular protection. The review further explores the protective effects of NSAIDs against cancer, citing numerous epidemiological studies that establish NSAIDs as chemopreventive agents. The use of NSAIDs, however, is limited by their toxicity, including gastrointestinal, renal, and other side effects.
The article then shifts its focus to the molecular targets of NSAIDs, starting with the COX cascade. The COX pathway produces prostaglandin H2 (PGH2), which is converted to various prostaglandins and thromboxane A2. The overexpression of COX-2 in many cancers led to the development of COX-2 inhibitors (COXIBs) for cancer prevention and treatment. However, the efficacy of COXIBs in cancer treatment has been questioned, as NSAIDs can exert anticancer effects even in the absence of COX-2. The authors also discuss the potential of PGE2 produced by tumor cells to contribute to immunosuppression in cancer patients.
The review then explores NSAID targets beyond COX, including NF-κB, PDK-1/Akt pathway, PPARs, MAPKs, Wnt/β-catenin pathway, phosphodiesterases, mTOR pathway, autophagy, cell kinetics, cytochrome c release, NSAID-activated gene (NAG-1), Ca2+ mobilization, inhibition of angiogenesis, and carbonic anhydrase inhibition. Each of these targets is discussed in detail, highlighting the role of NSAIDs in modulating these pathways and their implications in cancer prevention and treatment.
The final section of the review focuses on specialized pro-resolving mediators (SPMs), which are biosynthesized locally to promote the resolution of inflammation and tissue healing. The authors discuss different classes of SPMs, including lipoxins, resolvins, protectins, and maresins, and their potential in inhibiting cancer growth and metastasis. The concept of lipid class switching is introduced, where the lipid profile changes during the resolution phase of inflammation, leading to the production of SPMs. The anti-inflammatory actions of LXs/ATLs and resolvins are highlighted, along with their potential as therapeutic targets in cancer. The review concludes by emphasizing the need for developing effective and safe chemopreventive agents and identifying biomarkers that will aid in monitoring the response and selecting the best candidates for chemoprevention. The authors propose that targeting cancer-related inflammation and modulating the host microenvironment offer new perspectives in cancer chemotherapy. They also highlight the potential of aspirin-triggered SPMs in inducing cancer resolution, suggesting their utility for chemotherapy.
In summary, this comprehensive review provides a detailed overview of the mechanisms beyond COX inhibition that contribute to the anticancer effects of NSAIDs. It highlights the complex interplay between inflammation and cancer and suggests that targeting cancer-related inflammation and promoting the resolution phase of inflammation may offer new avenues for cancer therapy. The authors emphasize the need for further research in this area to develop effective and safe chemopreventive agents and identify biomarkers for personalized cancer treatment.
Ibuprofen
The reference text highlights that ibuprofen, a widely used nonsteroidal anti-inflammatory drug (NSAID), has demonstrated several key effects and potential mechanisms of action, particularly in the context of cancer prevention and treatment. The findings related to ibuprofen can be summarized as follows:
PPAR Activation: Ibuprofen, like aspirin and indomethacin, can activate PPARγ, a nuclear receptor that plays a role in cell proliferation, growth, and inflammation. The activation of PPARγ has been associated with anticarcinogenic properties, including promoting apoptosis and restricting cell growth. Therefore, ibuprofen's ability to activate PPARγ suggests a potential mechanism for its chemopreventive effects.
NAG-1 Induction: Ibuprofen has been shown to induce the expression of NSAID-activated gene (NAG-1), a protein with antitumorigenic properties. The induction of NAG-1 by ibuprofen is mediated through the p38 MAPK pathway. NAG-1 has been implicated in the inhibition of tumor growth and development in various cancers, including prostate cancer. In addition, ibuprofen-induced NAG-1 expression has been linked to the suppression of prostate cancer cell migration, suggesting a potential role in preventing metastasis.
Angiogenesis Inhibition: Ibuprofen has demonstrated the ability to inhibit angiogenesis, the process of new blood vessel formation that is crucial for tumor growth and metastasis. The study highlighted in the text showed that low-dose therapeutic levels of ibuprofen reduced tumor growth and metastases in colorectal cancer models by blocking angiogenesis, without increasing the risk of gastrointestinal toxicity. Similar results were observed in gastric adenocarcinoma, further supporting the anti-angiogenic potential of ibuprofen.
COX-Independent Effects: The text emphasizes that NSAIDs, including ibuprofen, can exert anticancer effects through mechanisms beyond COX inhibition. The study comparing the effects of celecoxib (a COX-2 selective inhibitor) and SC560 (a COX-1 selective inhibitor) showed similar results in colon cancer cell lines, regardless of COX-2 expression levels. Both NSAIDs induced cell cycle arrest and decreased survival rates, suggesting COX-independent mechanisms of action.
Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import (2014)
Key Findings:
Ibuprofen extends lifespan across multiple species:
The study found that ibuprofen increased the lifespan of three different model organisms:
In yeast (S. cerevisiae), 0.2 mM ibuprofen extended replicative lifespan by approximately 17% (p<0.0001).
In nematodes (C. elegans), 0.1 mM ibuprofen increased mean lifespan by about 12% (from 21.0 to 23.6 days, p<0.0001).
In fruit flies (D. melanogaster), 0.5 μM ibuprofen extended mean lifespan of females by about 17% (from 37.5 to 43.9 days, p<0.0001). In males, mean lifespan was extended but maximum lifespan was reduced.
Mechanism in yeast involves inhibition of tryptophan import:
Ibuprofen inhibited uptake of radiolabeled tryptophan in yeast cells.
Ibuprofen treatment reduced intracellular levels of aromatic amino acids, including tryptophan, by 15-20%.
Deletion of the high-affinity tryptophan permease gene TAT2 extended replicative lifespan by about 23% (p<0.0001).
Ibuprofen's lifespan extension was attenuated in tat2Δ cells and eliminated in tat1Δ tat2Δ double mutant cells that cannot import tryptophan.
Ibuprofen destabilizes the Tat2p tryptophan permease:
Ibuprofen reduced steady-state levels of Tat2p within 30-60 minutes of treatment.
The half-life of Tat2p was reduced from 28 minutes to 10 minutes by ibuprofen treatment.
A stabilized mutant version of Tat2p (Tat2p-5KR) prevented lifespan extension by ibuprofen.
Ibuprofen's effects are largely independent of TOR signaling:
Ibuprofen did not trigger other typical TOR pathway responses like Gln3p dephosphorylation or changes in gene expression.
Ibuprofen extended lifespan in tor1Δ, npr1Δ, gln3Δ, and gcn4Δ mutants.
Ibuprofen alters cell cycle progression:
At 0.2 mM, ibuprofen reduced cell size at birth by about 10% and moderately delayed G1 phase.
Higher doses (≥0.4 mM) significantly reduced growth rate.
Analysis of long-lived mutants reveals common cell cycle patterns:
Long-lived mutants tend to have slightly smaller birth size and reduced fitness/growth rate.
However, these relationships are constrained - the most extremely small or slow-growing mutants are not long-lived.
Long-lived mutants maintain efficient cell size control mechanisms.
Targeting amino acid transport may have general pro-longevity effects:
RNAi against putative C. elegans orthologs of TAT2 increased lifespan by 5-15%.
Stabilization of Tat2p increased birth size and suppressed lifespan extension in long-lived yeast mutants.
Key Conclusions:
Ibuprofen extends lifespan across evolutionarily divergent species through a mechanism independent of its known anti-inflammatory effects.
In yeast, ibuprofen's pro-longevity effects stem from inhibition of aromatic amino acid import, particularly tryptophan, by destabilizing the Tat2p permease.
This mechanism is largely independent of TOR signaling, though it may interact with or sensitize the TOR pathway.
Moderate reductions in cell size at birth and delays in G1 progression are common features of long-lived yeast mutants, but extreme changes are detrimental.
The results do not support the hypertrophy model of yeast replicative aging, which proposes lifespan is limited by reaching a maximum cell size.
The findings are more consistent with hormesis or antagonistic pleiotropy models of aging, where mild stresses or changes that are slightly detrimental in youth become beneficial in old age.
Targeting amino acid transport, particularly for aromatic amino acids like tryptophan, may be a conserved pro-longevity mechanism across species.
Ibuprofen boosts some organisms' life spans (2014)
A new study published in PLOS Genetics suggests that ibuprofen may increase longevity in certain organisms. Researchers from Texas A&M University found that when yeast, nematode worms, and fruit flies were given doses of ibuprofen comparable to human dosages, their lifespans increased. In yeast, ibuprofen extended lifespan by 17%, while worms and flies saw about a 10% increase. The study builds on previous research indicating that ibuprofen might have protective effects against age-related diseases like Alzheimer's and Parkinson's.
The mechanism behind ibuprofen's life-extending effects is not entirely clear, especially since yeast and nematodes lack the cyclooxygenase enzymes that the drug typically targets in humans. The researchers found that ibuprofen decreased tryptophan levels in yeast cells by 15-20%, speculating that this mild stress might trigger longevity-promoting responses. However, some experts caution against extrapolating these results to humans, noting the potential side effects of long-term ibuprofen use. The study suggests that further research, including testing on mice, could be valuable in exploring ibuprofen's potential anti-aging properties.
Nollen and Miller say the study supports testing ibuprofen in mice. The ITP did assess a related drug, nitroflurbiprofen, and found no change in longevity. However, Miller notes, those results don't rule out studies on ibuprofen because the two drugs are slightly different.
Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice (2017)
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