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Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G1 Microbial Products against Melanoma Cells.

ABSTRACT: Melanoma is the most serious type of skin cancer and remains highly drug-resistant. Therefore, the discovery of novel effective agents against melanoma is in high demand. Herein, we investigated the cytotoxic activities in melanoma cells and underlying molecular mechanisms of beauvericin (BEA) and its analogue beauvericin G1 (BEA G1), which are cyclohexadepsipeptides isolated from fungi. BEA and BEA G1 significantly suppressed the growth, clonogenicity, migration, and invasion of A375SM human melanoma cells and promoted caspase-dependent apoptosis through upregulation of death receptors, as well as modulation of pro- and anti-apoptotic Bcl-2 family members. Furthermore, the effects of BEA and BEA G1 were associated with the suppression of multiple molecular targets that play crucial roles in melanoma oncogenesis, including ERK, JNK, p38, NF-?B, STAT3, and MITF. Notably, the cytotoxic efficacy of BEA G1 against A375SM cells was stronger than that of BEA. These findings suggest that BEA and BEA G1 can be further investigated as potent cytotoxic natural compounds for the suppression of melanoma progression.

SUBMITTER: Lim HN

PROVIDER: S-EPMC7221855 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G1 Microbial Products against Melanoma Cells.

Lim Haet Nim HN Jang Jun-Pil JP Shin Hee Jeong HJ Jang Jae-Hyuk JH Ahn Jong Seog JS Jung Hye Jin HJ

Molecules (Basel, Switzerland) 20200423 8

Melanoma is the most serious type of skin cancer and remains highly drug-resistant. Therefore, the discovery of novel effective agents against melanoma is in high demand. Herein, we investigated the cytotoxic activities in melanoma cells and underlying molecular mechanisms of beauvericin (BEA) and its analogue beauvericin G1 (BEA G1), which are cyclohexadepsipeptides isolated from fungi. BEA and BEA G1 significantly suppressed the growth, clonogenicity, migration ...[more]

PMID: 32340351

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Project description:BackgroundAngelica shikokiana is a Japanese medicinal herb that is included among food and drug preparations protecting against cancer; however, there is no previous report about the cytotoxicity of A. shikokiana or its bioactive compounds.ObjectiveThis study was designed to investigate the cytotoxic activities of A. shikokiana methanol extract (AME) and its isolated compounds and to identify the molecular mechanisms of the cytotoxicity.Materials and methodsCytotoxicity and selectivity was investigated by measuring the IC50 values on five cancer cell lines; human hepatocellular carcinoma, rhabdomyosarcoma (RD), colorectal carcinoma, human epithelioma and human breast adenocarcinoma and one normal cell line; human lung fibroblasts. The effects on tubulin polymerization and histone deacetylase 8 (HDAC8), were examined to determine the mechanism of cytotoxicity. Docking study was designed to examine the binding affinity to the target molecules.ResultsMethanol extract and some of its isolated coumarins and flavonoids showed potent, selective cytotoxicity against cancer cell lines. AME and all isolated compounds inhibited tubulin polymerization. Angelicin and kaempferol-3-O-rutinoside were the most active compounds. Phenolic compounds and furanocoumarins showed binding affinity to colchicine binding site rather than the vinblastine binding site of tubulin microtubules. On the other side, quercetin, kaempferol, luteolin, chlorogenic acid, and methyl chlorogenate exhibited the strongest activity against HDAC8 and the highest affinity to trichostatin A binding site.ConclusionThese findings provide the first scientific evidence of the cytotoxicity of AME through inhibition of tubulin polymerization and HDAC8 activity through its coumarin and flavonoid content.SummaryThe present study provides for the first time a clue for the cytotoxic activities of the AME. Our results indicate that the cytotoxic activities are partially related to the ability of AME to inhibit tubulin polymerization and HDAC8 activity. Isolated compounds; Angelicin and kaempferol-3-O-rutinoside showed the strongest inhibition of tubulin polymerization through binding to colchicine binding domain of tubulin microtubules. Phenolic compounds; quercetin, luteolin, kaempferol, chlorogenic acid and methyl chlorogenate exhibited a strong inhibition of HDAC8 through binding to TSA binding site. This, however, further detailed pharmacological and in vivo studies should be the next step in evaluating the cytotoxic activities of AME and its active compounds that are currently ongoing. Abbreviations used: AME: Methanol extract of the aerial part of A. shikokiana, HDACs: Histone deacetylases,HDAC8: Histone deacetylase 8.

Project description:In order to select halophilic microorganisms as a source of compounds with cytotoxic activities, a total of 135 bacterial strains were isolated from water and sediment samples collected from the Zipaquirá salt mine in the Colombian Andes. We determined the cytotoxic effects of 100 crude extracts from 54 selected organisms on the adherent murine mammary cell carcinoma 4T1 and human mammary adenocarcinoma MCF-7 cell lines. These extracts were obtained from strains of Isoptericola, Ornithinimicrobium, Janibacter, Nesterenkonia, Alkalibacterium, Bacillus, Halomonas, Chromohalobacter, Shewanella, Salipiger, Martellela, Oceanibaculum, Caenispirillum and Labrenzia. The extracts of 23 strains showed an IC50 of less than 100 μg mL-1. They were subsequently analyzed by LC/MS allowing dereplication of 20 compounds. The cytotoxic effect was related to a complex mixture of diketopiperazines present in many of the extracts analyzed. The greatest cytotoxic activity against both of the evaluated cell lines was obtained from the chloroform extract of Labrenzia aggregata USBA 371 which had an IC50 < 6 μg mL-1. Other extracts with high levels of cytotoxic activity were obtained from Bacillus sp. (IC50 < 50 μg mL-1) which contained several compounds such as macrolactin L and A, 7-O-succinoylmacrolactin F and iturin. Shewanella chilikensis USBA 344 also showed high levels of cytotoxic activity against both cell lines in the crude extract: an IC50 < 15 μg mL-1 against the 4T1 cell line and an IC50 < 68 μg mL-1 against the MCF-7 cell line. Nesterenkonia sandarakina CG 35, which has an IC50 of 118 µg mL-1 against 4T1, is a producer of diketopiperazines and 1-acetyl-β-carboline. Also, Ornithinimicrobium kibberense CG 24, which has IC50 < 50 μg mL-1, was a producer of diketopiperazines and lagunamycin. Our study demonstrates that these saline environments are habitats of halophilic and halotolerant bacteria that have previously unreported cytotoxic activity.

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Dataset Information

Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G1 Microbial Products against Melanoma Cells.

Publications

Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G<sub>1</sub> Microbial Products against Melanoma Cells.

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