#1

Breaking off the discussion of other MEK inhibitors from the Tramatinib discussion here: A Combination of Rapamycin and Trametinib Extended Maximum Lifespan by up to 35%

I would really like the ITP to test Myricetin. Since it is a MEK inhibitor.

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A Combination of Rapamycin and Trametinib Extended Maximum Lifespan by up to 35%
#2

Myricetin inhibits MEK-1 (ref, ref) and parsley is a major source. I have no idea how much weaker the effect is though.

Quercetin too (ref).

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#3

Your 1st source isnā€™t loading for me, but Iā€™d say the 2nd source isnā€™t that useful. Docking scores are useful for motivating further study, but they donā€™t give a quantitative measure of potency or affinity (e.g IC50, Ki).

Myricetin does get mentioned in the study above (In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state):

The effects of the test substances on the senescent fibroblasts are summarized in Table 2. As can be seen from the table, NDGA had almost no effect on senescent phenotype, but decreased both short- and long-term survival. Myricetin had mild rejuvenating effect as judged by cell phenotype, but severely compromised long-term survival.

and

To investigate the mechanism of action of these compounds we performed pathway analysis. For this purpose we utilized transcriptional response data provided from Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset. After data processing (see Methods) we obtained pathway activation scores for 97 age-related pathways ( Supplementary Table S4). EGCG showed strong upregulation of cAMP pathway and inhibition of mitochondrial apoptosis and Ras pathways. Myricetin was found to upregulate ILK, DNA repair, cAMP and Hypoxia pathways. On the other hand, it severely suppressed PAK, IL-6, MAPK, Cellular senescence, p38, mTOR and several chemokine pathways. NAC showed strongly inhibition of pro-proliferative pathways like MAPK, AKT, p38, RAS, PAK, ERK and in turn activated p53, EGFR1, SMAD and Caspase signaling.

Myricetin also extends lifespan in C. Elegans: IJMS | Free Full-Text | Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16

#4

The present study is the first proof-of-concept of using U0126, an inhibitor of ERK1/2 phosphorylation, to increase elastin synthesis in a rat model deficient in aortic elastin content. Using vSMCs isolated from the aorta of the BN rat, we have shown that the marked increase in intracellular Ca2+ mediated by A23187 decreases the steady-state levels of several mRNAs encoding for proteins implicated in elastic fiber formation. We also showed that A23187 decreases both the transcription of the elastin gene and the stability of elastin mRNA. Furthermore, we provide evidence that the decrease in elastin gene transcription mediated by an increase in [Ca2+]i requires the phosphorylation of ERK1/2 and the recruitment of AP1 transcription factors. Our study specifically demonstrates for the first time that inhibition of ERK1/2 phosphorylation increases elastin synthesis both in vitro, in vSMCs, and in vivo, in the BN aorta, suggesting that inhibition of ERK1/2 phosphorylation might be a potential therapeutic strategy in vascular pathologies due to a deficit in elastin, such as SVAS.

Among molecules described to regulate elastin synthesis, we note that the downregulation of the elastin gene in rat fibroblasts by both bFGF and EGF is mediated by activation of the ERK1/2.13ā€“15 ERK1/2 activated by bFGF and EGF translocates to the nucleus where it accumulates, resulting in phosphorylation of Elk-1, which then induces c-fos expression that upregulates fra1.14,15 Both fra1 and c-fos can be heterodimerized with c-jun to form the complex AP1. In the human elastin gene promoter, an AP1-like site located at āˆ’564 to āˆ’558 bp has been described to repress elastin gene transcription mediated by recruitment of AP1 transcription factors.

In the present study we show that pharmacological inhibition of pro-proliferative pathways including H-Ras activation, Mek/Erk signaling, or cyclin D-cdk4 complex formation coincides with the recovery of normal deposition of elastic fibers in cultures of CS fibroblasts. To inhibit the initial proliferative signals induced by the hyperactive mutated H-Ras in CS cells, we used the antibiotic radicicol that emerged as a potent inhibitor of heat shock protein 90, the ubiquitous chaperone of numerous oncogenic proteins that ensures their proper folding and activation. It has been shown that the radicicol-dependent inhibition of heat shock protein 90 results in degradation of Raf and the consecutive inhibition of the Ras/Raf-Mek/Erk signaling cascade.

We found that experimental inhibition of H-Ras activity with radicicol not only quenched the heightened proliferation of CS fibroblasts but also induced recovery of their normal elastogenesis. Our finding encourages the use of this non-toxic macrolidic antibiotic in the future therapy of CS patients that would combat tumorigenesis as well as phenotypic abnormalities resulting from impaired elastogenesis. This claim can be endorsed by the fact that radicicol, in addition to inhibition of cancer cells proliferation, has also been shown to quench proliferation of activated inflammatory leukocytes and endothelial cells, thereby reducing inflammatory responses in atherosclerosis and experimental pneumonia. Radicicol has been also proposed as a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy. Importantly, we have also established that treatment with PD0332991 that inhibits the growth of solid tumors can also stimulate elastogenesis in cultures of normal and CS fibroblasts after Rb phosphorylation on Thr-821. Thus, this cdk4 inhibitor should also be considered in future therapies of CS patients.

To assess potential to address or slow the increasing burden of disease we investigated the potential of repurposing Trametinib as an anti-fibrotic and anti-inflammatory compound in a preliminary in vivo study using a mouse model of JEB. We found that over half of the mice treated with Trametinib experience a more severe phenotype, marked by a thinner epidermis, an increase in fibrotic marker Ī±SMA, and a non-significant decrease in the CD4 T cell infiltrate. In a combination treatment of Losartan and Trametinib, however, we found that Losartan ameliorated Trametinibā€™s adverse effects and restored epidermal thickness to the control phenotype, decreased Ī±SMA expression compared to Trametinib-only treatment, and CD4 expression steadily increasing in response to greater ear damage severity. Losartan is able to modulate some of Trametinibā€™s effects, potentially opening new lines of investigation to consider in terms of Losartanā€™s role in inflammatory conditions in EB research.

The effect of Trametinib on epidermal thickness is intriguing, and logic would dictate that inhibition of MEK in a highly proliferative tissue such as the epidermis would lead to a reduction in cellular content (in this case keratinocytes) and subsequent thickening. In the context of JEB, it is known that human patients have a stem cell defect, with laminin 332 contributing to stem cell maintenance [36,37], and this may well be compounded through the inhibition of proliferation. Indeed, it has been demonstrated that Trametinib inhibits dermal stem cells as well. Losartan on the other hand has demonstrated the ability to improve stem cell niches derived from adipose tissue and muscle, which provides another potential mechanism of action to explore in epidermal stem cells. Furthermore, the effects could be accelerated by environmental triggers leading to a worsening of the disease phenotype in the context of Trametinib treatment.

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#5

A mechanistic discussion about Myricetinā€™s potential as MEK inhibitor.

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#6

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
GSK3Ī² 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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#7

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.

[

  1. 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)


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  • 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.

[

  1. 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)


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  • 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.

[

  1. 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

[
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](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.

[

  1. Benefits and Risks of Taking Isoflavones - Verywell Health
    ](Benefits and Risks of Taking Isoflavones)


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  • 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.

[

  1. QUERCETIN: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews
    ](QUERCETIN: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews)


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2. Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update - MDPI


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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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#8

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-1Ī² in vitro, especially the inhibition of MMPs and inducible nitric oxide synthase (iNOS) through the attenuation of nuclear factor kappa-B (NF-ĪŗB) 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-1Ī² (5ng/mL). Effects of vorinostat on IL-1Ī²-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-ĪŗB 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-1Ī² stimulated chondrocytes was also suppressed by vorinostat. Interestingly, vorinostat selectively inhibited IL-1Ī²-induced p38 and ERK1/2 activation without affecting JNK activation. Furthermore, we observed that vorinostat inhibited NF-ĪŗB pathway by suppressing the degradation of I-ĪŗBĪ± and attenuating NF-ĪŗB 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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#9

All of them failed the ITP.

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#10

Try this link:

#11

It has low oral bioavailability.

#12

Noting that Berberine effects MEK /ERK1/2
Could Metformin also effect MEK /ERK1/2?

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#13

Would just be mechanistic speculation either way.

#14

Honokiol has evidence of anticancer activity in cell cultures similar to Trametinib, but it is impossible to achieve the 50uM concentration in organ tissues required since its solubility in water is 50ug/ml.

However, MCS Formulas, a Dutch company, sells a Lipo formulation that claims higher bioavailability : Honokiol Pro Liposomal, 60 Caps - MCS Formulas

Lipo formulations effectively bypass the gut barrier, so while Honokiol bioavailability would normally be limited to 50ug/ml x 3000ml (fluid intake) per day (around 150mg), you need to absorb around 3500-5000mg for a 70kg person to trigger anti-cancer effects so the Lipo formulation is the only way. I donā€™t have cancer, but am hoping to duplicate the MEK/ERK 1/2 inhibition of Trametinib for longevity with Honokiol (until I can talk myself into trying Trametinib), for which 225mg/day of Lipo Honokiol might be enough so I placed an order for 2x60 capsules (225mg of Lipo Honokiol) for $83.70 (including free shipping from Holland to USA).

BTW, I just discovered that MCS Formulas, a Dutch supplement company, was founded by Daniel S, PhD, the blogger of a popular cancer treatment website that focuses on supplements (or other prescription medications) to optimally complement standard-of-care cancer treatments like chemotherapy or radiation. He started the blog when his wife got brain cancer. Here is one article on his blog that impressed me : https://www.cancertreatmentsresearch.com/shutting-down-the-power-house-of-cancer-a-strategy-to-fight-cancer/?highlight=shutting%20down%20the%20powerhouse

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#15

Good info. Thank you.

I ordered liposomal apigenin. But will add honokiol, to try to achieve the strength of trametinibā€™s MEK inhibition. Will pulse three consecutive days a week, as people do with rapamycin.

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#16

Thank you for bringing MCS to my attention. They have an interesting line of products.

The liposomal honokiol product reminds me of an ARDD talk from a chinese oncology professor. He found that liposomal Honokiol (Given to enhance conventional cancer trestment) affected the hair follicles and new hair could grow. His english is a bit hard to understand, but the interesting part in the talk start at 13 min.

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#17

The slides show:

ChA regulates type I collage to improve skin condition
14:13

Hair growth effect by liposomal Honokiol
14:28

In the presentation, he said:

15:03
his cancer patient, who was bald, grew 3mm hair after two weeks of the drug.

He experimented with mice, and hair follicles almost doubled in two weeks.

17:30
Nitrate effectively protects against gastric mucosal damage under stress conditions.

"Salivary nitrate ā€œgoing up after people bungeeā€

17:37
Nitrate reduces obesity in mice by rebalancing the gut microbiota

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#18

Yes. Fascinating research.

But I would like to have more facts that support the indication, that honokiol might work through ways that include inhibiting MEK.

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