The Biological Activities of Sesterterpenoid-Type Ophiobolins

Tian, Wei; Deng, Zixin; Hong, Kui

doi:10.3390/md15070229

Cited by 57 publications

(57 citation statements)

References 81 publications

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“…Other successful natural products that have driven cancer therapies include taxol, vinblastin, anthracyclines, daunomycin and doxorubicin 62 . Many studies 40,42,43,47,63-66 have evaluated one such natural product, OpA, in cancer settings, predominantly using in vitro models, and, similar to our present study, these studies report IC 50 values in the low nanomolar range. Our work is one of the first to evaluate OpA in vivo and is the first to describe the impact of EMT on OpA sensitivity.…”

Section: Discussionsupporting

confidence: 82%

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Reisenauer

Tao

Song

et al. 2020

Preprint

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The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapy, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover, prolonged, sub-cytotoxic exposure to OpA is sufficient to reduce migration, sphere formation, and resistance to doxorubicin. OpA is well-tolerated in mice and treatment with OpA alone reduces tumor burden. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.in survival 14-17 . To improve TNBC patient outcomes, novel and specific approaches targeted at CSCs are needed.One proposed mechanism driving the emergence of CSC-like cells is the epithelialmesenchymal transition, EMT 18,19 . EMT is a trans-differentiation process characterized by spindle-like morphology, loss of apical-basal polarity, increased motility, and a tolerance to anoikis. These phenotypic shifts are driven by gene expression changes mediated by transcription factors Snail (SNAI1), Twist (TWIST1), and ZEB1, effects of which include upregulation of vimentin and N-cadherin, and downregulation of epithelial markers E-cadherin and miR-200c 20-26 . Cells that have undergone an EMT typically acquire CSC properties including decreased sensitivity to conventional chemotherapies used to treat TNBC. This chemoresistance is driven by drug efflux pumps, enhanced DNA repair capacity, mesenchymal-like properties, and epigenetic changes 16,27-32 . There are currently no approved therapies that specifically target CSCs. A leading pre-clinical compound is salinomycin, reported to decrease the subpopulation of CSCs, tumor initiating capability, and chemoresistance, with negligible side effects 33 . Other naturally occurring compounds such as curcumin, and quercetin have been reported to reduce the effects of EMT by inhibiting key proteins associated with migration (Snail, MMP-2/9), anoikis tolerance (Bcl-2), cell-to-cell adhesion (N-cadherin), and signaling cascades (JAK/STAT, ERK) 34-37 .Ophiobolin A (OpA) is a natural product produced from fungi in the genera Aspergillus, Bipolaris, Cephalosporium, Cochliobolus, is a secondary metabolite that has long been studied for its phytotoxic effects in a variety of plants and has begun to be evaluated as a cytotoxic compound 38 . Recently published cell Western blotting and antibodiesCells were lysed in the presence of 100 microliters radio-immunoprecipitation (RIPA) buffer containing protease inhibitors (Alfa Aesar, Stoughton, MA, USA) on ice. Protein was quantified using the Bradford Assay (BioRad,...

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Section: Discussionsupporting

confidence: 82%

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Reisenauer

Tao

Song

et al. 2020

Preprint

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“…and ophiobolins from marine-derived fungus Aspergillus spp. [4][5][6]. Ophiobolins (Ophs) are a very rare group of sesterterpenoids that bear a unique 5-8-5 tricarbocyclic in structure [5].…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6]. Ophiobolins (Ophs) are a very rare group of sesterterpenoids that bear a unique 5-8-5 tricarbocyclic in structure [5]. At present, 72 Ophs have been reported including 35 Ophs which were produced by marine-derived fungus [5,[7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Ophiobolins (Ophs) are a very rare group of sesterterpenoids that bear a unique 5-8-5 tricarbocyclic in structure [5]. At present, 72 Ophs have been reported including 35 Ophs which were produced by marine-derived fungus [5,[7][8][9]. The family shows significant inhibitory effects on the growth of a variety of cancer cells, drug-resistant cells, and cancer stem cells [5].…”

Section: Introductionmentioning

confidence: 99%

“…At present, 72 Ophs have been reported including 35 Ophs which were produced by marine-derived fungus [5,[7][8][9]. The family shows significant inhibitory effects on the growth of a variety of cancer cells, drug-resistant cells, and cancer stem cells [5]. In total, 41 cell lines have been tested for 26 Ophs with the IC 50 values ranging from 0.08 µM to 85 ± 12 µM [5], which is considered to be potential drug candidates for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

Tian

Deng

et al. 2019

Marine Drugs

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Sesterterpene MHO7 derived from mangrove fungus is a novel estrogen receptor degrader for the treatment of breast cancer. To explore its safety and pharmacokinetics in vivo, Log P/D values, stability in simulated gastric/intestinal (SGF/SIF), toxicity, and pharmacokinetics studies were carried mainly by liquid chromatography technique coupled with tandem mass spectrometry (LC–MS/MS) method in mice, and the effect of MHO7 on mice gut microbiota at different time points was revealed by 16S rRNA sequencing. Log P/D values ranged 0.93–2.48, and the compound in SGF and SIF is stable under the concentration of 5 mM·L−1. The maximum tolerance dose (MTD) of oral administration in mice was 2400 mg·kg−1. The main pharmacokinetics parameters were as following: Cmax of 1.38 μg·mL−1, Tmax of 8 h, a half-life (t1/2) of 6.97 h, an apparent volume of mean residual time (MRT) of 8.76 h, and an area under the curve (AUC) of 10.50 h·μg·mL−1. MHO7 displayed a wide tissue distribution in mice, with most of the compound in liver (3.01 ± 1.53 μg·g−1) at 1 h, then in fat (5.20 ± 3.47 μg·g−1) at 4 h, and followed by reproductive organs with the concentrations of 23.90 ± 11.33 μg·g−1,13.69 ± 10.29 μg·g−1, 1.46 ± 1.23 μg·g−1, and 0.36 ± 0.46 μg·g−1 at 8, 12, 20 and 30 h, respectively. The most influenced genera of gut microbiome belonged to phylum Firmicutes (21 of 28), among which 18 genera originated from the order Clostridiales, class Clostridia, and families of Ruminococcaceae (11 of 18) and Lachnospiraceae (4 of 18). These results provide that MHO7 is suitable for oral administration in the treatment of breast cancer with the target organs of reproductive organs and regulation on Ruminococcaceae and Lachnospiraceae.

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Biological Control and Use of Bioherbicides

2023

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The Biological Activities of Sesterterpenoid-Type Ophiobolins

Cited by 57 publications

References 81 publications

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Toxicity, Pharmacokinetics, and Gut Microbiome of Oral Administration of Sesterterpene MHO7 Derived from a Marine Fungus

Biological Control and Use of Bioherbicides

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