The aspirin metabolite salicylate inhibits lysine acetyltransferases and MUC1 induced epithelial to mesenchymal transition

Fernandez, Harvey R.; Lindén, Sara K.

doi:10.1038/s41598-017-06149-4

Cited by 21 publications

(20 citation statements)

References 66 publications

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“…Therefore, it has been hypothesised that these effects are related to the inhibition of HATs (Table 2). In vitro tests confirmed that salicylate directly inhibited the activity of PCAF, TIP60, and MOF in PC-3 prostate cancer cells, probably by reversing the epithelial-mesenchymal transition [28]. It has been proven that the strategy of HAT blocking using bi-substrate inhibitors is a very effective way of obtaining high affinity and selectivity of action by bioactive compounds.…”

Section: Histone Acetyltransferasesmentioning

confidence: 86%

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Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Kopytko

Piotrowska

Janisiak

et al. 2021

IJMS

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Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.

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Section: Histone Acetyltransferasesmentioning

confidence: 86%

Section: Histone Acetyltransferasesmentioning

confidence: 99%

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Kopytko

Piotrowska

Janisiak

et al. 2021

IJMS

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“…The chemopreventive and anticarcinogenic activities of ASA have largely been attributed to COX inhibition resulting in reduced synthesis of PGE 2 , which is upregulated in cancers (3) and implicated in multiple carcinogenic processes (5–8). In addition, ASA has been shown to activate the ATM kinase (35) and block NFκB (36) and Akt pathways (37). Other activities of ASA include activation of AMPK (9) that may regulate mTOR pathways involved in autophagy (11) and apoptosis (10) in cancer cells, and inhibition of heparanase that was associated with reduced angiogenesis and growth of tumor xenografts (22).…”

Section: Discussionmentioning

confidence: 99%

Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo

Kumar

Rahman

Tyagi

et al. 2018

Cancer Prevention Research

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There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E (PGE) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE and activation of AMPK and reduces growth of some melanoma tumors This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans..

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“…Despite the extensive body of retrospective clinical evidence suggesting an association of aspirin with improved PrCa outcomes, very few preclinical studies examined the effects of aspirin in PrCa models and even fewer focused specifically on SAL. High dose SAL (0.5‐20 mM) was shown to suppress growth in PrCa cell models and block endothelial to mesenchymal transition (EMT) in PC3 cells . In cervical cancer SAL was shown to enhance the anti‐proliferative and pro‐apoptotic effects of RT but, to date, SAL has not been investigated in combination with RT in pre‐clinical models of PrCa.…”

Section: Discussionmentioning

confidence: 99%

“…High dose SAL (0.5-20 mM) was shown to suppress growth in PrCa cell models 35,36 and block endothelial to mesenchymal transition (EMT) in PC3 cells. 37 In cervical cancer SAL was shown to enhance the antiproliferative and pro-apoptotic effects of RT 38 but, to date, SAL has not been investigated in combination with RT in pre-clinical models of PrCa.…”

Section: Salicylate Inhibits De Novo Lipogenesis (Dnl) In Pc3 Cellsmentioning

confidence: 99%

Salicylate enhances the response of prostate cancer to radiotherapy

et al. 2019

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Background Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose‐escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP‐activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl‐CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT. Methods Androgen‐insensitive (PC3) and ‐sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5 g/kg salsalate (SAL pro‐drug dimer) one week prior to a single dose of 0 or 10 Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK‐mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT. Results SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti‐tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation. Conclusions Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa in combination with RT.

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The aspirin metabolite salicylate inhibits lysine acetyltransferases and MUC1 induced epithelial to mesenchymal transition

Cited by 21 publications

References 66 publications

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo

Salicylate enhances the response of prostate cancer to radiotherapy

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