Chemistry and biology of ophiobolin A and its congeners

Masi, Marco; Dasari, Ramesh; Evidente, Antonio; Mathieu, Véronique; Kornienko, Alexander

doi:10.1016/j.bmcl.2019.02.007

Cited by 49 publications

(66 citation statements)

References 63 publications

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“…Ophiobolin A (OpA) is a natural product produced by fungi in the genera Aspergillus, Bipolaris, Cephalosporium, Cochliobolus, and Drechslera 37 . This sesterterpenoid (25-carbons) is a secondary metabolite that has long been studied for its phytotoxic effects in a variety of plants and has begun to be evaluated for its anti-cancer properties 37 .…”

Section: Introductionmentioning

confidence: 99%

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

Reisenauer

Tao

Das

et al. 2021

Sci Rep

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The epithelial–mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, 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 suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. 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.

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Section: Introductionmentioning

confidence: 99%

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

Reisenauer

Tao

Das

et al. 2021

Sci Rep

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“…D. gigantea is closely related to the Bipolaris genus, which is widely studied because many species belonging to it are responsible for severe diseases of cereal crops. These species are also studied for the production of phytotoxic secondary metabolites often involved in infection processes, among which sesterterpenoid ophiobolins are well-known for their interesting biological properties [30,31].…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis Defense against the Pathogenic Fungus Drechslera gigantea Is Dependent on the Integrity of the Unfolded Protein Response

et al. 2021

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Drechslera gigantea Heald & Wolf is a worldwide-spread necrotrophic fungus closely related to the Bipolaris genus, well-known because many member species provoke severe diseases in cereal crops and studied because they produce sesterpenoid phytoxins named ophiobolins which possess interesting biological properties. The unfolded protein response (UPR) is a conserved mechanism protecting eukaryotic cells from the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). In plants, consolidated evidence supports the role of UPR in the tolerance to abiotic stress, whereas much less information is available concerning the induction of ER stress by pathogen infection and consequent UPR elicitation as part of the defense response. In this study, the infection process of D. gigantea in Arabidopsis thaliana wild type and UPR-defective bzip28 bzip60 double mutant plants was comparatively investigated, with the aim to address the role of UPR in the expression of resistance to the fungal pathogen. The results of confocal microscopy, as well as of qRT-PCR transcript level analysis of UPR genes, proteomics, microRNAs expression profile and HPLC-based hormone analyses demonstrated that ophiobolin produced by the fungus during infection compromised ER integrity and that impairment of the IRE1/bZIP60 pathway of UPR hampered the full expression of resistance, thereby enhancing plant susceptibility to the pathogen.

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Section: Introductionmentioning

confidence: 99%

“…Ophiobolin A (OpA) is a natural product produced from fungi in the genera Aspergillus, Bipolaris, Cephalosporium, Cochliobolus , and Drechslera 38 . This sesterterpenoid (25-carbons) 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 culture-based experiments describe a role for OpA in motility inhibition 39 , membrane depolarization 40-43 , roles in inflammation 44 , and reduction in stemness 45 .…”

Section: Introductionmentioning

confidence: 99%

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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Chemistry and biology of ophiobolin A and its congeners

Cited by 49 publications

References 63 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

Arabidopsis Defense against the Pathogenic Fungus Drechslera gigantea Is Dependent on the Integrity of the Unfolded Protein Response

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

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