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

Cancer Medicine
Abdullah Al EmranHelmut Schaider

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 als...Continue Reading

References

Jun 6, 2002·The Journal of Biological Chemistry·Karin MoellingMarc Schweneker
May 14, 2005·CA: a Cancer Journal for Clinicians·Irene M GhobrialAlex A Adjei
Feb 13, 2008·Cell·Asako Sakaue-SawanoAtsushi Miyawaki
May 11, 2010·Biochemical Pharmacology·Gajanan S InamdarGavin P Robertson
Jun 7, 2011·The New England Journal of Medicine·Paul B ChapmanUNKNOWN BRIM-3 Study Group
Aug 15, 2013·Archives of Pharmacal Research·Jong-Rung TsaiPo-Len Liu
Jan 28, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Helen RizosGeorgina V Long
Jun 7, 2014·Pigment Cell & Melanoma Research·Nikolas K HaassWolfgang Weninger
Jun 14, 2014·Proceedings of the National Academy of Sciences of the United States of America·Marina K AyrapetovBrendan D Price
Jun 25, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Gerald S FalchookRichard F Kefford
Jun 14, 2016·Cell Reports·Jennifer M SpangleMyles Brown
Apr 27, 2017·Frontiers in Pharmacology·Lian-Xiang LuoLiang Liu
May 27, 2017·The Journal of Biological Chemistry·Andrew P TrottaJerry E Chipuk
Jun 22, 2017·Methods in Molecular Biology·Loredana SpoerriNikolas K Haass

❮ Previous
Next ❯

Citations

Mar 31, 2021·The Journal of Investigative Dermatology·Abdullah Al EmranJessamy C Tiffen
Apr 6, 2021·Frontiers in Pharmacology·Yiping LinYing Song
Aug 28, 2021·Diagnostics·Antonios RevythisStergios Boussios

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
fluorescence microscopy

Software Mentioned

ImageJ

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis