Abstract
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.
Highlights
Melanoma patients harbor BRAF mutations in 40%‐60% resulting in constitutive activation of prosurvival signaling through the MAPK pathway.[1]
Cells were stained with 0.5% crystal violet (n = 3, biological replicates). (B) In a separate experiment, WM1366 and WM164 cells were exposed to DMSO, 30 μmol L−1 magnolol, 10 μmol L−1 SC79 or a combination of 30 μmol L−1 magnolol/10 μmol L−1 SC79 for 48 h
Actin was used as a loading control. (C) WM164 and WM1366 cells were treated with DMSO, 30 μmol L−1 magnolol, 1 μmol L−1 MK2206 or 30 μmol L−1 magnolol/1 μmol L−1 MK2206 for 72 h
Summary
Melanoma patients harbor BRAF mutations in 40%‐60% resulting in constitutive activation of prosurvival signaling through the MAPK pathway.[1]. Honokiol and its derivatives have been shown to be potent GABAA receptor agonists[7] and inverse cannabinoid 2 receptor agonists.[8] honokiol activates Sirtuin‐3 (SIRT3, mitochondria‐dependent deacetylase) which can act as a tumor suppressor via decrease in ROS production and regulating HIF1.9 Along this, magnolol plays an important role to decimate cancer cells by inducing apoptosis through increased production of caspases‐3, 8, and 9, suppression of Bcl‐2 expression and activation of death receptor and mitochondrial pathways.[10] As melanoma patients experience most often a disease relapse during targeted therapies, plant‐derived lead structures may possess potential to be developed into a useful addition to existing therapies. Combinatorial treatment of low‐dose magnolol and targeted therapy or chemotherapy led to an increase in cell death in BRAF‐ and NRAS‐mutant melanoma cells demonstrating a synergistic effect
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