Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma
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 offi...
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| Format: | Article |
| Language: | English |
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Wiley
2019-03-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.1978 |
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| author | Abdullah Al Emran Brinda Reddy Chinna Chowdary Farzana Ahmed Heinz Hammerlindl Antje Huefner Nikolas K. Haass Wolfgang Schuehly Helmut Schaider |
| author_facet | Abdullah Al Emran Brinda Reddy Chinna Chowdary Farzana Ahmed Heinz Hammerlindl Antje Huefner Nikolas K. Haass Wolfgang Schuehly Helmut Schaider |
| author_sort | Abdullah Al Emran |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3aa2130ffe474e608238e42be0c263ba |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2019-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-3aa2130ffe474e608238e42be0c263ba2025-01-31T08:47:43ZengWileyCancer Medicine2045-76342019-03-01831186119610.1002/cam4.1978Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanomaAbdullah Al Emran0Brinda Reddy Chinna Chowdary1Farzana Ahmed2Heinz Hammerlindl3Antje Huefner4Nikolas K. Haass5Wolfgang Schuehly6Helmut Schaider7Dermatology Research Centre The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaDermatology Research Centre The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaThe University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaDermatology Research Centre The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaDepartment of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences University of Graz Graz Styria AustriaThe University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaDepartment of Pharmacognosy Karl‐Franzens University Graz Styria AustriaDermatology Research Centre The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland AustraliaAbstract 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.https://doi.org/10.1002/cam4.1978AktBRAFhistone markMagnolia officinalismagnololmelanoma |
| spellingShingle | Abdullah Al Emran Brinda Reddy Chinna Chowdary Farzana Ahmed Heinz Hammerlindl Antje Huefner Nikolas K. Haass Wolfgang Schuehly Helmut Schaider Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma Cancer Medicine Akt BRAF histone mark Magnolia officinalis magnolol 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 | Akt BRAF histone mark Magnolia officinalis magnolol melanoma |
| url | https://doi.org/10.1002/cam4.1978 |
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