Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro
We previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystall...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00115/full |
| _version_ | 1811215939787554816 |
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| author | Michelle M. Martínez-Montemayor Taotao Ling Ivette J. Suárez-Arroyo Gabriela Ortiz-Soto Camille L. Santiago-Negrón Mercedes Y. Lacourt-Ventura Anibal Valentín-Acevedo Walter H. Lang Fatima Rivas |
| author_facet | Michelle M. Martínez-Montemayor Taotao Ling Ivette J. Suárez-Arroyo Gabriela Ortiz-Soto Camille L. Santiago-Negrón Mercedes Y. Lacourt-Ventura Anibal Valentín-Acevedo Walter H. Lang Fatima Rivas |
| author_sort | Michelle M. Martínez-Montemayor |
| collection | DOAJ |
| description | We previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds. We report the structures of the seven most abundant GLE compounds and their selective efficacy against triple negative (TNBC) and inflammatory breast cancers (IBC) and other human cancer cell types (solid and blood malignancies) to illustrate their potential as anti-cancer agents. Three of the seven compounds (ergosterol, 5,6-dehydroergosterol and ergosterol peroxide) exhibited significant in vitro anti-cancer activities, while we report for the first time the structure elucidation of 5,6-dehydroergosterol from Ganoderma lucidum. We also show for the first time in TNBC/IBC cells that ergosterol peroxide (EP) displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation, and PARP cleavage. EP decreased migratory and invasive effects of cancer cells while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc in the tested IBC cells. Our investigation also indicates that these compounds induce reactive oxygen species, compromising cell fate. Furthermore, we generated a superior derivative, ergosterol peroxide sulfonamide, with improved potency in IBC cells and ample therapeutic index (TI > 10) compared to normal cells. The combined studies indicate that EP from Ganoderma lucidum extract is a promising molecular scaffold for further exploration as an anti-cancer agent. |
| first_indexed | 2024-04-12T06:31:53Z |
| format | Article |
| id | doaj.art-d007338dd510499e9c088d509da2d89c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T06:31:53Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d007338dd510499e9c088d509da2d89c2022-12-22T03:44:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-02-011010.3389/fphar.2019.00115432597Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitroMichelle M. Martínez-Montemayor0Taotao Ling1Ivette J. Suárez-Arroyo2Gabriela Ortiz-Soto3Camille L. Santiago-Negrón4Mercedes Y. Lacourt-Ventura5Anibal Valentín-Acevedo6Walter H. Lang7Fatima Rivas8Cancer Research Unit, Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, Puerto RicoDepartment of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United StatesCancer Research Unit, Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, Puerto RicoCancer Research Unit, Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, Puerto RicoDepartment of Biology, University of Puerto Rico, Bayamón, Puerto RicoCancer Research Unit, Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, Puerto RicoDepartment of Microbiology and Immunology, School of Medicine, Universidad Central del Caribe, Bayamón, Puerto RicoDepartment of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United StatesDepartment of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United StatesWe previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds. We report the structures of the seven most abundant GLE compounds and their selective efficacy against triple negative (TNBC) and inflammatory breast cancers (IBC) and other human cancer cell types (solid and blood malignancies) to illustrate their potential as anti-cancer agents. Three of the seven compounds (ergosterol, 5,6-dehydroergosterol and ergosterol peroxide) exhibited significant in vitro anti-cancer activities, while we report for the first time the structure elucidation of 5,6-dehydroergosterol from Ganoderma lucidum. We also show for the first time in TNBC/IBC cells that ergosterol peroxide (EP) displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation, and PARP cleavage. EP decreased migratory and invasive effects of cancer cells while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc in the tested IBC cells. Our investigation also indicates that these compounds induce reactive oxygen species, compromising cell fate. Furthermore, we generated a superior derivative, ergosterol peroxide sulfonamide, with improved potency in IBC cells and ample therapeutic index (TI > 10) compared to normal cells. The combined studies indicate that EP from Ganoderma lucidum extract is a promising molecular scaffold for further exploration as an anti-cancer agent.https://www.frontiersin.org/article/10.3389/fphar.2019.00115/fullGanoderma lucidumergosterol peroxidebreast cancerEP derivativesnatural product |
| spellingShingle | Michelle M. Martínez-Montemayor Taotao Ling Ivette J. Suárez-Arroyo Gabriela Ortiz-Soto Camille L. Santiago-Negrón Mercedes Y. Lacourt-Ventura Anibal Valentín-Acevedo Walter H. Lang Fatima Rivas Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro Frontiers in Pharmacology Ganoderma lucidum ergosterol peroxide breast cancer EP derivatives natural product |
| title | Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro |
| title_full | Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro |
| title_fullStr | Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro |
| title_full_unstemmed | Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro |
| title_short | Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro |
| title_sort | identification of biologically active ganoderma lucidum compounds and synthesis of improved derivatives that confer anti cancer activities in vitro |
| topic | Ganoderma lucidum ergosterol peroxide breast cancer EP derivatives natural product |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00115/full |
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