Anticancer activity of Ophiobolin A, isolated from the endophytic fungus <i>Bipolaris setariae</i>

Bhatia, Dimple; Dhar, Payal; Mutalik, Varun; Deshmukh, Sunil K.; Verekar, Shilpa A.; Desai, Dattatraya C.; Kshirsagar, Rajendra; Thiagarajan, Padma; Agarwal, Veena R.

doi:10.1080/14786419.2015.1062760

Cited by 41 publications

(25 citation statements)

References 13 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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“…Such induction is observed after the exposure of tumor cells to ophiobolin A (OP-A), a BKCa inhibiting metabolite with an anticancer activity from the fungus Bipolaris sp. [40, 120, 121]. BKCa inhibition was proposed to give rise to excessive K + in the ER and mitochondria.…”

Section: Vacuolization and Known Cell Death Pathwaysmentioning

confidence: 99%

“…Presumably, a long-term increase in Ca 2+ concentration in the cytoplasm is the cause of cell death [40]. Apart from that, the cytotoxic effect of OP-A on tumor cells is attributed to its capacity to suppress the main oncogenic pathways: PI3K/mTOR, Ras/Raf/ERK, and CDK/RB [120]. …”

Section: Vacuolization and Known Cell Death Pathwaysmentioning

confidence: 99%

Cytoplasmic vacuolization in cell death and survival

et al. 2016

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Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

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“…Ophiobolin A showed cytotoxicity in the L1210 cell line [31] , inhibited solid and haematological cancer cell proliferation, induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells [32] . Ophiobolin A can be incorporated into novel chemoembolization particles for the reduction in cell viability of rhabdomyosarcoma cancer (RD) cells [33] , also can inhibit growth even induce cell death of several mammalian cancer cell lines irrespective of their multidrug resistance phenotypes and their resistance levels to pro-apoptotic stimuli [20] .…”

Section: Antitumor Activities (Cytotoxicity)mentioning

confidence: 97%

A Brief Review on Structure-Bioactivity Relationship Study of Ophiobolins and Derivatives

Ren¹,

Yang²,

Zhang³

et al. 2018

CMRJ

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Ophiobolins show a broad-spectrum inhibitory activity against nematodes, fungi, bacteria, and cytotoxic activity. Now many ophiobolin and their derivatives have been identified, nevertheless, there are few studies on structure-activity relationships for this class of compound. This review aims at summarizing published researches of ophiobolins and their derivatives, including the source, structure, bioactivity, the mode of action and the possible factors that cause the different bioactivity. In view of the fact that the activity of ophiobolins were generally higher than 6-epi-ophiobolins, ophiobolin O, K and 6-epi-ophiobolin O, K were studied as an example. The geometries, bond lengths, bond orders of the four compounds have been investigated at B3LYP/6-31+G(dip) level by density functional theory (DFT). The DFT analysis show that the ophinbolins steric of function group related to C (7) were much lower than 6-epi-ophiobolins, it suggested that C-H was the key bioactive group. The low steric reactive function group can be made to maximize contact with the target and thereby enhance the biological activity. It proposed a new pathway for the design and synthesis of the active molecule.

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Anticancer activity of Ophiobolin A, isolated from the endophytic fungus Bipolaris setariae

Cited by 41 publications

References 13 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

Cytoplasmic vacuolization in cell death and survival

A Brief Review on Structure-Bioactivity Relationship Study of Ophiobolins and Derivatives

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