Even I, experimenter and canary in the coal that I am, stay away from interventions that have scary and possibly profound side effects.
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Table 2
Selection of serine/threonine-specific kinases (STKs) shown to be inhibited by natural compounds.
| Protein Kinase | Natural Compound |
|---|---|
| PI3K | Apigenin, Fisetin, Naringenin, Silibinin, Parthenolide, Oridonin, Honokiol, Genistein, EGCG, Taxifolin, Ellagic acid, Emodin, Curcumin |
| AKT | Apigenin, Fisetin, Quercetin, Naringenin, Silibinin, Parthenolide, Oridonin, Curcumin EGCG, Luteolin, Resveratrol, Genistein, Taxifolin, Wedelolactone, Ellagic acid, Emodin, Harmine, Curcumin |
| mTOR | Apigenin, Quercetin, Genistein, EGCG, Curcumin, Oridonin, Silibinin, Wedelolactone, Curcumin |
| GSK3β | Apigenin, Curcumin, Berberine, Resveratrol, Curcumin, Luteolin, Quercetin, Curcumin |
| CK2 | Apigenin, Coumestrol, Resorufin, Gallaflavin, Fisetin, Nortangeretin, Ellagic acid |
| RAF | Curcumin, EGCG, Resveratrol, Parthenolide |
| MEK/ERK1/2 | Apigenin, Quercetin, Silibinin, Oridonin, Genistein, Parthenolide, Genistein, Honokiol, Cyanidin, Berberine, Quercetin, Ellagic acid, Emodin |
| PKC | Apigenin, Wedelolactone, Curcumin |
| CamKK | Apigenin, Curcumin, Resveratrol, Berberine, EGCG (stimulation) |
| IKK | Apigenin, Wedelolactone |
| JNK | Apigenin, Quercetin, Silibinin, Cyanidin, Parthenolide, Hesperetin |
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There are several naturally occurring compounds found in foods that exhibit similar activity to trametinib, a MEK inhibitor targeting the MAPK signaling pathway. These compounds primarily exert their effects through inhibiting various components of this pathway, leading to potential anticancer, anti-inflammatory, and antioxidant properties.
Some notable examples include:
- Curcumin: Found in turmeric, curcumin is a potent inhibitor of multiple kinases within the MAPK pathway. It has been shown to suppress tumor growth and metastasis in various cancers.
[
- Molecular Mechanisms of Anti-metastatic Activity of Curcumin - Anticancer Research
](https://ar.iiarjournals.org/content/36/11/5639#:~:text=Studies%20have%20shown%20that%20curcumin,cells%20and%20preventing%20invasion%20and)
- Resveratrol: Abundant in grapes and red wine, resveratrol exhibits anti-inflammatory and antioxidant effects by modulating the MAPK pathway. It has been linked to reduced risk of cardiovascular diseases and certain cancers.
[
- Resveratrol Inhibits LPS-Induced MAPKs Activation via Activation of the Phosphatidylinositol 3-Kinase Pathway in Murine RAW 264.7 Macrophage Cells | PLOS ONE
](Resveratrol Inhibits LPS-Induced MAPKs Activation via Activation of the Phosphatidylinositol 3-Kinase Pathway in Murine RAW 264.7 Macrophage Cells)
- Epigallocatechin gallate (EGCG): The major polyphenol in green tea, EGCG possesses strong antioxidant properties and can inhibit specific kinases in the MAPK pathway. It has been associated with anti-inflammatory effects and potential chemopreventive properties against cancer.
[
- The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review - MDPI
](IJMS | Free Full-Text | The Potential of Epigallocatechin Gallate (EGCG) in Targeting Autophagy for Cancer Treatment: A Narrative Review
[
- Genistein: This isoflavone found in soy products is known for its phytoestrogenic properties. It also demonstrates inhibitory effects on the MAPK pathway, contributing to its potential anticancer and anti-inflammatory effects.
[
- Benefits and Risks of Taking Isoflavones - Verywell Health
](Benefits and Risks of Taking Isoflavones)
- Quercetin: Widely distributed in fruits and vegetables, quercetin is a flavonoid with antioxidant and anti-inflammatory properties. It can modulate the MAPK pathway and has been studied for its potential in cancer prevention and treatment.
[
- QUERCETIN: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews
](QUERCETIN: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews)
2. Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update - MDPI
It is important to note that while these natural compounds show promising activity against the MAPK pathway, their efficacy and potency might not be as strong as trametinib. Further research is needed to fully understand their therapeutic potential and optimal dosages for specific conditions.
Please note that this information is notintended as medical advice. If you have any questions or concerns, it is recommended to consult with a qualified healthcare professional.
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Methylation of CpG repeats in the upstream/promoter regions of genes is an established mechanism of gene silencing in many cell types. DNA methylation results in the recruitment of histone deacetylases (HDACs) to promoter regions, thereby repressing expression of genes. General inhibitors of class I and II HDACs (HDACi), such as sodium butyrate and suberoylanilide hydroxamic acid, suppress the growth of prostate cancer cells in vitro and in vivo. In this study, we investigated the mechanism of re-expression of silenced cell cycle inhibitors and retinoic acid receptor B2 (RARB2). HDACi inhibited cell cycle progression, and reversed promoter methylation and silencing of three tumor suppressor genes: RARB2 and the cell cycle regulating cyclin-dependent kinase inhibitors p16 and p21. HDACi repressed MAP kinase I (ERK) activation and down-regulated DNA (cytosine-5-)-methyltransferase 1 (DNMT1) levels. Direct inhibition of ERK activity similarly decreased DNMT1 protein levels and reversed the basal hypermethylation of the promoters and silencing of the RARB2, p21 and p16 tumor suppressor genes. Suppression of DNMT1 level by siRNA also reversed methylation of these tumor suppressor genes with similar kinetics. Collectively, these data demonstrate that HDACi, by inhibiting ERK activity, regulate DNMT1 and ultimately DNA methylation. These results demonstrate that HDACs regulate gene methylation, in addition to the established and reciprocal ability of CpG methylation to recruit HDACs to repress transcription.
Overproduction of nitric oxide (NO) and matrix metalloproteinases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). In present study, we investigated whether vorinostat can inhibit the catabolic effects of IL-1β in vitro, especially the inhibition of MMPs and inducible nitric oxide synthase (iNOS) through the attenuation of nuclear factor kappa-B (NF-κB) and mitogen activated protein kinase (MAPK) pathways in human chondrocytes. Human OA chondrocytes were either left untreated or treated with various concentrations of vorinostat followed by incubation with IL-1β (5ng/mL). Effects of vorinostat on IL-1β-induced gene and protein expression of iNOS, MMP-1, MMP-13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) were verified by quantitative real time-PCR and Western blot analysis. Production of NO, MMP-1, MMP-13 and TIMP-1 released in culture supernatant was estimated using commercially available kits. The roles of NF-κB and MAPK pathways in the regulation of targeted genes and the mechanism involved in vorinostat mediated modulation of these genes were determined by Western blot using specific antibodies. We found that vorinostat down-regulated iNOS, MMP-1 and MMP-13 expression and up-regulated TIMP-1 expression in human OA chondrocytes. In addition, the release of NO, MMP-1 and MMP-13 secreted from IL-1β stimulated chondrocytes was also suppressed by vorinostat. Interestingly, vorinostat selectively inhibited IL-1β-induced p38 and ERK1/2 activation without affecting JNK activation. Furthermore, we observed that vorinostat inhibited NF-κB pathway by suppressing the degradation of I-κBι and attenuating NF-κB p65 translocation to the nucleus. These results suggest that vorinostat may be a promising therapeutic agent for the prevention and treatment of OA.
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All of them failed the ITP.
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Try this link:
It has low oral bioavailability.
There have been 17 clinical trials so far involving Trametinib, usually with other cancer therapies. Here is a full list, and links to more details:
Clinical Trials Using Trametinib
Clinical trials are research studies that involve people. The clinical trials on this list are studying trametinib. All trials on the list are NCI-supported clinical trials, which are sponsored or otherwise financially supported by NCI.
https://www.cancer.gov/research/participate/clinical-trials/intervention/trametinib
This is interesting:
Trametinib
Drug design and preclinical activity
Trametinib (GSK1120212) is a reversible allosteric inhibitor of MEK1 and MEK2 activation and kinase activity, with preclinical evidence of MAPK inhibition and growth inhibition in BRAFV600E melanoma cell lines and xenografts (23).
Clinical trials
Phase I trial.
The phase I trial commenced in 2008, and of 206 patients, 97 had metastatic melanoma with no restriction of eligibility by somatic mutations, for example BRAF mutations. Thirty-six patients had BRAF-mutant melanoma and 39 had wild-type BRAF melanoma (7 of whom had an NRAS-mutant melanoma), 6 had unknown BRAF status, and 16 patients had uveal melanoma (24, 25). Dose titration commenced at 0.125 mg, with dose-limiting toxicities observed at total daily doses of 3 mg and 4 mg, and the RP2D was 2 mg once daily. At this dose, analysis of biopsies taken early during treatment and compared with baseline samples showed that there was effective inhibition of MAPK signaling as measured by phosphorylated extracellular signalâregulated kinase (ERK; 60% reduction), effective inhibition of proliferation (Ki67 reduced by 80%), and an increase in cell-cycle inhibition (p27 increased by 170%).
The most frequent toxicities included MEK inhibitor class-like toxicities such as an acneiform rash (88%), diarrhoea, peripheral oedema, and fatigue (Table 1). In the trial of 206 patients with solid tumors, ocular toxicities occurred in 15% (n = 31) of patients, including reversible central serous retinopathy (n = 3) and rarely irreversible retinal vein occlusion (n = 1). Transient left ventricular dysfunction was noted in 8% (n = 16) of patients. Twelve percent of patients treated at 2 mg required dose reductions, most commonly due to rash.
Phase III trial (METRIC).
Toxicities were similar to those in the earlier trials, including MEK inhibitor class-like effects such as rash, diarrhoea, peripheral oedema, hypertension, and transient mild cardiac dysfunction. Chorioretinopathy was rare (<1% grade 3), and no cases of retinal vein occlusion were reported. Most toxicities were mild and did not require drug discontinuation; however, 27% of patients underwent dose reduction.
Table 1.
Summary of dabrafenib and trametinib clinical trial results
TrametinibClinicalTrialSummary.pdf (46.6 KB)
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A 2022 Phase 2/3 Clinical Trial of Trametinib, and the associated side effects recorded. Daily dosing of trametinib definitely has an ugly side effect profile. The key question is whether periodic (e.g. once weekly) dosing might greatly reduce or eliminate most of these side effect risks.
The Study used oral trametinib 2 mg once daily (trametinib group)
The toxic effects observed in patients in the trametinib group of our study were similar to previous MEK inhibitor studies in patients with other cancer types, such as melanoma. However, clinical management of adverse events can be challenging, with fatigue, skin rash, and gastrointestinal side-effects occurring most commonly, and dose reductions being necessary for many patients. For adverse events of special interest, the incidence of retinal events was 2%, and, although 8% of patients had decreased ejection fraction, they often recovered, and some patients were able to be rechallenged.
Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02175-9/fulltext#tables
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Yes, like fisetin, curcumin and other similar substances the absorption issue has to be adressed. My first option is piperine.
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ChatGPT on other MEK inhibitors:
Please list all the drugs that are classified as MEK inhibitors
ChatGPT
MEK (Mitogen-Activated Protein Kinase Kinase) inhibitors are a class of drugs used primarily in the treatment of cancer, as they target the MEK proteins involved in the MAPK/ERK signaling pathway, which is often dysregulated in tumors. As of my last update, here are some well-known MEK inhibitors:
- Trametinib (Trade name: Mekinist) - Approved for the treatment of melanoma, non-small cell lung cancer (NSCLC), and certain types of thyroid cancer.
- Cobimetinib (Trade name: Cotellic) - Used in combination with vemurafenib for the treatment of BRAF V600 mutation-positive melanoma.
- Binimetinib (Trade name: Mektovi) - Approved for the treatment of BRAF V600E or V600K mutation-positive melanoma, often in combination with encorafenib.
- Encorafenib (Trade name: Braftovi) - Although primarily a BRAF inhibitor, itâs often used in combination with MEK inhibitors like binimetinib for better efficacy in treating melanoma.
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Some very good results (significant reduction of side effects) from intermittent dosing of trametinib:
Intermittent dosing in these examples is defined as: a five-week-on and three-week-off schedule.
In February 2016, after almost a full year of continuous daily dosing, she started a 3-week drug holiday before resuming treatment using an intermittent schedule of 5 weeks of treatment followed by a 3-week break, per 8-week cycle. This approach was associated with a considerable reduction in her fatigue and an improvement of her well-being.
Like patient 2, this patient noted considerable improvement in her sense of well-being after converting to an intermittent therapy regimen. On treatment for now 18 months (13 months on intermittent drug administration), this patient continues to tolerate dabrafenib and trametinib at full dose on the five-week-on, three-week-off schedule and has resumed work unencumbered by symptoms from her disease or from the treatment.
Both patients experienced considerably fewer adverse events and no cumulative toxicity with intermittent dosing, permitting them to resume active lifestyles largely unencumbered by the anticancer treatment.
Results: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing.
Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports
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Here is a phase 2 clinical trial looking at intermittent dosing with trametinib:
Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial
The intermittent dosing arm used the same doses during weeks 1 and 5â8 of each 8-week cycle (5 weeks on). No therapy was given during weeks 2â4 on the intermittent therapy arm (3 weeks off).
Adverse events.
All adverse events assessed as possibly, probably, and definitely related to study treatment. On the continuous therapy arm, 38 patients (36%) experienced grade 3 adverse events, and 7 (7%) experienced grade 4 events, while on the intermittent therapy arm, 31 patients (31%) experienced grade 3 adverse events, and 3 (3%) experienced grade 4 events (p=0.46 for grade 3, p=0.33 for grade 4). The most common grade 3â4 adverse event across both arms was fatigue. There was a significant difference in the incidence of grade 3 and 4 pyrexia, (6 patients on continuous dosing vs 1 patient on intermittent dosing, p<0.001).
There has been at least one additional (2024) clinical study using intermittent dosing schedules, and larger numbers of patients, for trametinib, but it is behind a paywall. If anyone can access and post it please do, as it would give us more information on the side effect reduction from continuous to intermittent dosing schedules.
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(Deleted by Author.)
I donât think there is any hurry⌠weâre all going to get some extra time from the rapamycin, and it seems some de-risking could and should be done by longevity researchers on trametinib before even periodic dosing is tested by biohackers:
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Good points. Best to avoid for now.
In patients, trametinib is used for the treatment of metastatic melanomas [76] and has also been used in clinical trials for the treatment of solid tumours [77] [78]. At a dose of 2 mg trametinib once a day, the drug was well tolerated with only small side effects including skin rash, diarrhoea, fatigue and retinopathy [77]. Average peak plasma levels in patients receiving 2mg trametinib daily were between 5.5 and 7.5ng/ml [77] [78], which is significantly higher than the 0.1ng/ml in mice fed with the lifespan extending dose of 1.44mg trametinib/kg food. In a mouse model of mucosal melanoma, administering trametinib via oral gavage resulted in an average peak concentration of 23.8ng/ml [79], which is more than 200-fold the concentration required for lifespan extension. Although trametinib plasma levels might not be directly comparable between chronic feeding and acute application, these results suggest that higher trametinib doses are required for its anti-cancer effect than for lifespan extension. Consistently, tumour progression or load were not significantly changed in long-lived mice treated with trametinib. The effect of trametinib at the chosen concentration of 1.44mg/kg on lifespan and health at old age was mild, indicating that we underdosed and that the optimal dose for lifespan extension might be higher. In the pre-test, a dose of 2.88 mg/kg trametinib did not cause detrimental side effects. Thus, this can be used as a guideline for future studies to optimize the dose of trametinib for maximal lifespan extension. Additionally, it would be interesting to determine whether late-onset or intermittent feeding recapitulates the effects of continuous trametinib treatment on mouse lifespan, as this would be key to enhance adherence and feasibility of trametinib treatment in humans.
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The half-life is also long, so you can take it once a week or every two weeks without any hassle.
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The half-life of trametinib is 4-5 days, almost twice as long as rapamycin. If you take rapamycin every day, you may experience a lot of side effects. But once a week, it causes almost no side effects. Couldnât a similar situation occur for trametinib taken once every two weeks? Since no one has tried it, we naturally have no information. But I think there is an unnecessary fear about this.
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There is definitely a reasonable argument that dosing once every week or two with trametinib could have very low or minimal side effects, but it would be good for a medical group to do such a test with regular blood and functional monitoring for the more serious potential risks; retinal issues, heart issues (ejection fraction), blood pressure, kidney function, anemia, etc⌠It would be very hard, if not impossible, for a biohacker to be able to do this type of monitoring over a period of many weeks or months, so I really think we need to lobby a longevity research group to start a small clinical study to do this, and publish the results.
@Livin and @Vlasko , given your experience with, and knowledge about, this drug what are you opinions? How would you design a study to test its safety in a pulsed once weekly or once every two week dosing schedule?
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