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

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

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Cancer Medicine
Volume: 8
Number: 3
Page Range: pp. 1186-1196
Date: 2019
Divisions: Immune Imaging
Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1002/cam4.1978
ISSN: 2045-7634
Date Deposited: 17 Dec 2020 03:30

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.

Keywords: Magnolia officinalis; Akt; BRAF; NRAS; PI3K; histone mark; magnolol; melanoma.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Emran, Abdullah Al
Chinna Chowdary, Brinda Reddy
Ahmed, Farzana
Hammerlindl, Heinz
Huefner, Antje
Haass, Nikolas K.
Schuehly, Wolfgang
Schaider, Helmut
Last Modified: 17 Dec 2020 03:30

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