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Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma

Most BRAF‐mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant‐derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis,...

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Autores principales: Emran, Abdullah Al, Chinna Chowdary, Brinda Reddy, Ahmed, Farzana, Hammerlindl, Heinz, Huefner, Antje, Haass, Nikolas K., Schuehly, Wolfgang, Schaider, Helmut
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434221/
https://www.ncbi.nlm.nih.gov/pubmed/30793515
http://dx.doi.org/10.1002/cam4.1978
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author Emran, Abdullah Al
Chinna Chowdary, Brinda Reddy
Ahmed, Farzana
Hammerlindl, Heinz
Huefner, Antje
Haass, Nikolas K.
Schuehly, Wolfgang
Schaider, Helmut
author_facet Emran, Abdullah Al
Chinna Chowdary, Brinda Reddy
Ahmed, Farzana
Hammerlindl, Heinz
Huefner, Antje
Haass, Nikolas K.
Schuehly, Wolfgang
Schaider, Helmut
author_sort Emran, Abdullah Al
collection PubMed
description Most BRAF‐mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant‐derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis, induced G1 arrest, apoptosis and cell death in BRAF‐ and NRAS‐mutant melanoma cells at low concentration, with no effect in BRAF‐ and NRAS wild‐type melanoma cells and human keratinocytes. This was confirmed in a 3D spheroid model. The apoptosis‐inducing effect of magnolol was completely rescued by activating Akt suggesting a mechanism relying primarily on Akt signaling. Magnolol significantly downregulated the PI3K/Akt pathway which led to a global decrease of the active histone mark H3K4me3. Alongside, the repressive histone mark H3K9me3 was increased as a response to DNA damage. Magnolol‐induced alterations of histone modifications are reversible upon activation of the Akt pathway. Magnolol‐induced a synergistic effect in combination with either BRAF/MEK inhibitors dabrafenib/trametinib or docetaxel at a lower concentration than usually applied in melanoma patients. Combination of magnolol with targeted therapy or chemotherapy also led to analogous effects on histone marks, which was rescued by Akt pathway activation. Our study revealed a novel epigenetic mechanism of magnolol‐induced cell death in melanoma. Magnolol might therefore be a clinically useful addition to BRAF/MEK inhibitors with enhanced efficacy delaying or preventing disease recurrence.
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spelling pubmed-64342212019-04-15 Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma Emran, Abdullah Al Chinna Chowdary, Brinda Reddy Ahmed, Farzana Hammerlindl, Heinz Huefner, Antje Haass, Nikolas K. Schuehly, Wolfgang Schaider, Helmut Cancer Med Cancer Biology Most BRAF‐mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant‐derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis, induced G1 arrest, apoptosis and cell death in BRAF‐ and NRAS‐mutant melanoma cells at low concentration, with no effect in BRAF‐ and NRAS wild‐type melanoma cells and human keratinocytes. This was confirmed in a 3D spheroid model. The apoptosis‐inducing effect of magnolol was completely rescued by activating Akt suggesting a mechanism relying primarily on Akt signaling. Magnolol significantly downregulated the PI3K/Akt pathway which led to a global decrease of the active histone mark H3K4me3. Alongside, the repressive histone mark H3K9me3 was increased as a response to DNA damage. Magnolol‐induced alterations of histone modifications are reversible upon activation of the Akt pathway. Magnolol‐induced a synergistic effect in combination with either BRAF/MEK inhibitors dabrafenib/trametinib or docetaxel at a lower concentration than usually applied in melanoma patients. Combination of magnolol with targeted therapy or chemotherapy also led to analogous effects on histone marks, which was rescued by Akt pathway activation. Our study revealed a novel epigenetic mechanism of magnolol‐induced cell death in melanoma. Magnolol might therefore be a clinically useful addition to BRAF/MEK inhibitors with enhanced efficacy delaying or preventing disease recurrence. John Wiley and Sons Inc. 2019-02-21 /pmc/articles/PMC6434221/ /pubmed/30793515 http://dx.doi.org/10.1002/cam4.1978 Text en © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Emran, Abdullah Al
Chinna Chowdary, Brinda Reddy
Ahmed, Farzana
Hammerlindl, Heinz
Huefner, Antje
Haass, Nikolas K.
Schuehly, Wolfgang
Schaider, Helmut
Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title_full Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title_fullStr Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title_full_unstemmed Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title_short Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
title_sort magnolol induces cell death through pi3k/akt‐mediated epigenetic modifications boosting treatment of braf‐ and nras‐mutant melanoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434221/
https://www.ncbi.nlm.nih.gov/pubmed/30793515
http://dx.doi.org/10.1002/cam4.1978
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