Publications by authors named "Joanna E Burdette"

121 Publications

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion.

Cancers (Basel) 2021 Apr 16;13(8). Epub 2021 Apr 16.

Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.
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http://dx.doi.org/10.3390/cancers13081925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073317PMC
April 2021

Semisynthetic Derivatives of the Verticillin Class of Natural Products through Acylation of the C11 Hydroxy Group.

ACS Med Chem Lett 2021 Apr 19;12(4):625-630. Epub 2021 Mar 19.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.

The verticillins, a class of epipolythiodioxopiperazine alkaloids (ETPs) first described 50 years ago with the discovery of verticillin A (), have gained attention due to their potent activity against cancer cells, noted both in vitro and in vivo. In this study, the complex scaffold afforded through optimized fermentation was used as a feedstock for semisynthetic efforts designed to explore the reactivity of the C11 and C11' hydroxy substituents. Functionality introduced at these positions would be expected to impact not only the potency but also the pharmacokinetic properties of the resulting compound. With this in mind, verticillin H () was used as a starting material to generate nine semisynthetic analogues (-) containing a variety of ester, carbonate, carbamate, and sulfonate moieties. Likewise, verticillin A succinate () was synthesized from to demonstrate the successful application of this strategy to other ETPs. The synthesized compounds and their corresponding starting materials (i.e., and ) were screened for activity against a panel of melanoma, breast, and ovarian cancer cell lines: MDA-MB-435, MDA-MB-231, and OVCAR3. All analogues retained IC values in the nanomolar range, comparable to, and in some cases more potent than, the parent compounds.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040035PMC
April 2021

Advancements in microfluidic systems for the study of female reproductive biology.

Endocrinology 2021 Apr 14. Epub 2021 Apr 14.

Department of Pharmaceutical Sciences, University of Illinois at Chicago.

The female reproductive tract is a highly complex physiological system, which consists of ovaries, fallopian tubes, uterus, cervix, and vagina. An enhanced understanding of the molecular, cellular, and genetic mechanisms of the tract will allow for the development of more effective assisted reproductive technologies, therapeutics, and screening strategies for female specific disorders. Traditional two-dimensional and three-dimensional static culture systems may not always reflect the cellular and physical contexts or physicochemical microenvironment necessary to understand the dynamic exchange that is crucial for the functioning of the reproductive system. Microfluidic systems present a unique opportunity to study the female reproductive tract as these systems recapitulate the multicellular architecture, contacts between different tissues, and microenvironmental cues that largely influence cell structure, function, behavior, and growth. This review discusses examples, challenges, and benefits of using microfluidic systems to model ovaries, fallopian tubes, endometrium, and placenta. Additionally, this review also briefly discusses the use of these systems in studying effects of endocrine disrupting chemicals and diseases such as ovarian cancer, preeclampsia, and PCOS.
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http://dx.doi.org/10.1210/endocr/bqab078DOI Listing
April 2021

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2.

Cell Death Dis 2021 Apr 7;12(4):375. Epub 2021 Apr 7.

Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.
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http://dx.doi.org/10.1038/s41419-021-03663-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027874PMC
April 2021

(9βH)- and 17-Nor-Pimaranes from .

J Nat Prod 2021 Apr 26;84(4):949-955. Epub 2021 Mar 26.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.

Eleven pimarane-type diterpenoids were isolated from the tubers of , including three new compounds, icacinlactone M (), icacinlactone H 2--β-d-glucopyranoside (), and icacinlactone N 3--β-d-glucopyranoside (), together with an artifact of acrenol (). Among the known structures, icacinlactone A (), icacinlactone B (), icacinlactone H (), 12-hydroxyicacinlactone A (), 14α-methoxyhumirianthol (), and annonalide () are reported from for the first time, whereas icacinol () has previously been found in this plant. Icacinol, 14α-methoxyhumirianthol, and annonalide displayed moderate cytotoxic activity in a panel of human cancer cell lines.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01131DOI Listing
April 2021

Opportunities and Limitations for Assigning Relative Configurations of Antibacterial Bislactones using GIAO NMR Shift Calculations.

J Nat Prod 2021 Apr 25;84(4):1254-1260. Epub 2021 Mar 25.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States.

Four new bislactones, dihydroacremonol (), clonostachyone (), acremodiol B (), and acremodiol C (), along with one known compound, hymeglusin (), were isolated from cultures of two fungal strains (MSX59876 and MSX59260). Both strains were identified based on phylogenetic analysis of molecular data as spp.; yet, they biosynthesized a suite of related, but different, secondary metabolites. Given the challenges associated with elucidating the structures and configurations of bislactones, GIAO NMR calculations were tested as a complement to traditional NMR and HRESIMS experiments. Fortuitously, the enantiomer of the new natural product () was known as a synthetic compound, and the predicted configuration from GIAO NMR calculations (i.e., for the relative configuration) and optical rotation calculations (i.e., for the absolute configuration) matched those of the synthesis product. These results engendered confidence in using similar procedures, particularly the mixture of GIAO NMR shift calculations coupled with an orthogonal technique, to predict the configuration of -; however, there were important limitations, which are discussed for each of these. The metabolites displayed antimicrobial activities, with compounds and being the most potent against with MICs of 1 and 4 μg/mL, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108483PMC
April 2021

Limonoids and other triterpenoids from Entandrophragma angolense.

Fitoterapia 2021 Feb 12;150:104846. Epub 2021 Feb 12.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States. Electronic address:

Four new compounds (1-4) were isolated from the stem bark of Entandrophragma angolense along with eleven known structures (5-15). The chemical structures were elucidated on the basis of spectroscopic and HRMS data, and the absolute configuration was established with the aid of electronic circular dichroism. Compound 5 displayed moderate cytotoxicity against MDA-MB-231, OVCAR3, MDA-MB-435, and HT29 cell lines, with IC values ranging from 2.0-5.9 μM.
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http://dx.doi.org/10.1016/j.fitote.2021.104846DOI Listing
February 2021

Thielavins: tuned biosynthesis and LR-HSQMBC for structure elucidation.

J Antibiot (Tokyo) 2021 May 25;74(5):300-306. Epub 2021 Jan 25.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA.

A series of thielavins I, V, and Q (1-3) and the previously undescribed thielavin Z (4) were isolated from cultures of a fungal Shiraia-like sp. (strain MSX60519) that were grown under a suite of media and light conditions, with enhanced biosynthesis noted using rice as a substrate with 12:12 h light:dark cycles. Conversely, oatmeal medium and continuous white light-emitting diode light exposure negatively affected the production of these compounds, at least by strain MSX60519. The structure of 4 was determined using NMR spectroscopic data and mass fragmentation patterns. Of note, the utility of LR-HSQMBC and NOESY NMR experiments in the structural elucidation of these hydrogen-deficient natural products was demonstrated. Compounds 1-4 exhibited cytotoxic activity at the micromolar level against human breast, ovarian, and melanoma cancer cell lines.
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http://dx.doi.org/10.1038/s41429-021-00405-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084880PMC
May 2021

Cytotoxic Naphthoquinone Analogues, Including Heterodimers, and Their Structure Elucidation Using LR-HSQMBC NMR Experiments.

J Nat Prod 2021 03 2;84(3):771-778. Epub 2020 Oct 2.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27412, United States.

Approximately 1700 naphthoquinones have been reported from a range of natural product source materials, but only 283 have been isolated from fungi, fewer than 75 of those were dimers, and only 2 were heterodimers with a head-to-tail linkage. During a search for anticancer leads from fungi, a series of new naphthoquinones (-), including two heterodimers ( and ), were isolated from sp. (strain MSX63693). In addition, the previously reported 5-hydroxy-6-(1-hydroxyethyl)-2,7-dimethoxy-1,4-naphthalenedione (), misakimycin (), 5-hydroxy-6-[1-(acetyloxy)ethyl]-2,7-dimethoxy-1,4-naphthalenedione (), 6-ethyl-2,7-dimethoxyjuglone (), and kirschsteinin () were isolated. While the structure elucidation of - was achieved using procedures common for natural products chemistry studies (high-resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D NMR), the elucidation of the heterodimers was facilitated substantially by data from the long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) experiment. The absolute configuration of was established by analysis of the measured vs calculated ECD data. The racemic mixture of was established via X-ray crystallography of an analogue that incorporated a heavy atom. All compounds were evaluated for cytotoxicity against the human cancer cells lines MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovarian), where the IC values ranged between 1 and 20 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005429PMC
March 2021

Phenethyisoquinoline alkaloids from the leaves of Androcymbium palaestinum.

Fitoterapia 2020 Oct 21;146:104706. Epub 2020 Aug 21.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, United States of America.

Thirteen compounds were isolated from the methanolic extract of the leaves of Androcymbium palaestinum Baker (Colchicaceae). Of these, three were new, two were new natural products, and eight were known. The new isolated compounds were (+)-1-demethylandrocine (5), (-)-andropalaestine (8), and (+)-2-demethyl-β-lumicolchicone (10), while the new natural products were (+)-O-methylkreysigine-N-oxide (3) and (+)-O,O-dimethylautumnaline (9). Moreover, two known compounds are reported for the first time from this species, specifically (-)-colchicine (11) and (-)-3-demethyldemecolcine (13). The structures of the isolated compounds were elucidated using a series of spectroscopic and spectrometric techniques, principally HRESIMS, 1D-NMR (H and C NMR) and 2D-NMR (COSY, edited-HSQC, and HMBC). ECD spectroscopy was used for assigning the absolute configurations of compounds 3, 5, and 10. The cytotoxic activities of the isolated compounds were evaluated using the MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovary) cancer cell lines. Compound 11 was the most potent against all tested cell lines, with IC values of 12, 95 and 23 nM, respectively.
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http://dx.doi.org/10.1016/j.fitote.2020.104706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871506PMC
October 2020

Exposure of human fallopian tube epithelium to elevated testosterone results in alteration of cilia gene expression and beating.

Hum Reprod 2020 09;35(9):2086-2096

Department of Pharmaceutical Biosciences, University of Illinois at Chicago, Chicago, IL 60607, USA.

Study Question: How does exposure to a testosterone rich environment affect the function and gene expression of human fallopian tube epithelium (hFTE)?

Summary Answer: Elevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating.

What Is Known Already: The presence of estrogen in the follicular phase of the menstrual cycle increases the human fallopian tube ciliary beating frequency. The luteal phase, triggered by ovulation and increasing progesterone, is marked by a decrease in ciliary beating. Women with polycystic ovarian syndrome (PCOS) may have twice the serum level of testosterone than ovulatory women. To date, the effect of elevated androgens on the function of the human fallopian tube is not well-understood. We chose to examine the impact of elevated testosterone on hFTE.

Study Design, Size, Duration: A prospective basic science study of human fallopian tube specimens from reproductive-aged women undergoing benign gynecologic surgery was performed. Fallopian tube removal at a large US academic center was collected and provided to us to continue with epithelium isolation and culturing. A total of 12 patients were analyzed in the study.

Participants/materials, Setting, Methods: Fallopian tube epithelium was isolated and exposed to two different conditions: normal with low testosterone concentration of 0.8 nM and PCOS-like, with high testosterone concentration of 2 nM. The study was conducted in both static and dynamic conditions in microfluidic devices for a total of 14 days, after which the tissue was collected for processing including RNA extraction, quantitative PCR and immunohistochemistry. After the first 7 days of each experiment, a sample of tissue from each condition was imaged to quantify cilia beating frequency.

Main Results And The Role Of Chance: hFTE exposed to the 2 nM testosterone displayed slower cilia beating, inhibited estrogen signaling and decreased expression of the ciliary marker FOXJ1 when compared to stimulation with 0.8 nM testosterone.

Large Scale Data: N/A.

Limitations, Reasons For Caution: The in vivo response to elevated testosterone may differ from in vitro studies. RNA amount was limited from tissue cultured in the microfluidic devices as compared to static culture.

Wider Implications Of The Findings: Understanding elevated testosterone in tubal function may explain an additional contribution to subfertility in women with PCOS and other hyper-androgen disorders, aside from oligo-ovulation. Furthermore, this adds to the body of literature of fallopian tube function using a microfluidic device.

Study Funding/competing Interest(s): NIH grants: UH3 ES029073 and R01 CA240301. There are no competing interests.
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http://dx.doi.org/10.1093/humrep/deaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550267PMC
September 2020

Corrigendum to '19-nor-pimaranes from Icacina trichantha' [Fitoterapia. 144 (2020) 104612].

Fitoterapia 2020 Oct 23;146:104656. Epub 2020 Jun 23.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.

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http://dx.doi.org/10.1016/j.fitote.2020.104656DOI Listing
October 2020

19-nor-pimaranes from Icacina trichantha.

Fitoterapia 2020 Jul 11;144:104612. Epub 2020 May 11.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States of America.

Four new unusual 19-nor-pimarane-type diterpenes were isolated from the tuber of Icacina trichantha (Icacinaceae, Oliv.). The structures were elucidated based on spectroscopic and HRMS analysis. The absolute configurations were determined by electronic circular dichroism. All four compounds are structural analogues of icacinol and humirianthol, but do not demonstrate the same cytotoxic activity. A plausible biogenetic pathway is proposed.
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http://dx.doi.org/10.1016/j.fitote.2020.104612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384768PMC
July 2020

Metabolites from the Marine-Facultative sp. MEXU 27854 and MEXU 29901 from Caleta Bay, Mexico.

Tetrahedron Lett 2019 Jun 20;60(25):1649-1652. Epub 2019 May 20.

Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, México.

During our ongoing research on fungal strains from unexplored sources, the reinvestigation of the CHCl-MeOH extract of the marine-facultative sp. MEXU 27854 yielded a new -methyl cyclic pentapeptide () along with known butyrolactone II and PF1233 A. In addition, from the marine-facultative MEXU 29901, a new alternariol glucoside, 10-[-D-(4-methoxyl-glucopyranosyl)]-4--methylalternariol () and known alternariol 4-methyl ether, alternariol and beauvericin, were isolated. The structures of and were established by detailed spectroscopic data, and their absolute configuration was ascertained by Marfey's analysis and HRESIMS-MS/MS data for , and by chemical degradation and optical rotation analysis for .
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http://dx.doi.org/10.1016/j.tetlet.2019.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207482PMC
June 2019

Laxaphycins B5 and B6 from the cultured cyanobacterium UIC 10484.

J Antibiot (Tokyo) 2020 08 31;73(8):526-533. Epub 2020 Mar 31.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Two laxaphycin type-B cyclic dodecapeptides, laxaphycins B5 and B6, were obtained from UIC 10484, a freshwater cf. Phormidium sp. Analysis using the 16S rRNA sequence found UIC 10484 to clade with UIC 10045, a known laxaphycin type-A and -B producer, and MS/MS analysis revealed the presence of two novel laxaphycin type-B compounds. The structures of the metabolites were elucidated using 2D NMR and MS/MS. The absolute configurations of the amino acids were determined by advanced Marfey's analysis. Both metabolites were evaluated against the same three cancer cell lines. The IC of both laxaphycins B5 and B6 was near 1 μM against breast cancer MDA-MB-231, melanoma MDA-MB-435, and ovarian cancer OVCAR3 cell lines.
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http://dx.doi.org/10.1038/s41429-020-0301-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338234PMC
August 2020

Baicalein Is a Phytohormone that Signals Through the Progesterone and Glucocorticoid Receptors.

Horm Cancer 2020 04 7;11(2):97-110. Epub 2020 Mar 7.

Department of Pharmaceutical Sciences, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.

While flavonoids have been studied extensively for estrogen receptor activity, they have not been well studied for their ability to modify progesterone receptor (PR) and glucocorticoid receptor (GR) signaling. Three flavonoid compounds, tangeretin, wogonin, and baicalein, were selected for testing for PR and GR activity based on their structural similarity to known phytoprogesterone-like compounds. Each compound was docked in the binding pocket of PR and GR. Of these compounds, baicalein was predicted to be most likely to bind to both receptors. A fluorescence polarization competitive binding assay for PR and GR confirmed that baicalein binds to both the PR and GR with IC values of 15.30 μM and 19.26 μM, respectively. In Ishikawa PR-B and T47D cells, baicalein acted as a PR antagonist in a hormone response element (HRE) luciferase (Luc) assay. In OVCAR5 cells, which only express GR, baicalein was a GR agonist via an HRE/Luc assay and induced GR target genes, FKBP5 and GILZ. RU486, a PR and GR antagonist, abrogated baicalein's activity in OVCAR5 cells, confirming baicalein's activity is mediated through the GR. In vivo, baicalein administered intraperitoneally to female mice twice a week for 4 weeks at a dose of 25 mg/kg induced the GR target gene GILZ in the reproductive tract, which was blocked by RU486. In summary, baicalein has PR antagonist and GR agonist activity in vitro and demonstrates GR agonist activity in the uterus in vivo.
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http://dx.doi.org/10.1007/s12672-020-00382-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236083PMC
April 2020

Na/K-ATPase-Targeted Cytotoxicity of (+)-Digoxin and Several Semisynthetic Derivatives.

J Nat Prod 2020 03 25;83(3):638-648. Epub 2020 Feb 25.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

(+)-Digoxin () is a well-known cardiac glycoside long used to treat congestive heart failure and found more recently to show anticancer activity. Several known cardenolides (-) and two new analogues, (+)-8(9)-β-anhydrodigoxigenin () and (+)-17--20,22-dihydro-21α-hydroxydigoxin (), were synthesized from and evaluated for their cytotoxicity toward a small panel of human cancer cell lines. A preliminary structure-activity relationship investigation conducted indicated that the C-12 and C-14 hydroxy groups and the C-17 unsaturated lactone unit are important for to mediate its cytotoxicity toward human cancer cells, but the C-3 glycosyl residue seems to be less critical for such an effect. Molecular docking profiles showed that the cytotoxic and the noncytotoxic derivative bind differentially to Na/K-ATPase. The HO-12β, HO-14β, and HO-3'aα hydroxy groups of (+)-digoxin () may form hydrogen bonds with the side-chains of Asp121 and Asn122, Thr797, and Arg880 of Na/K-ATPase, respectively, but the altered lactone unit of results in a rotation of its steroid core, which depotentiates the binding between this compound and Na/K-ATPase. Thus, was found to inhibit Na/K-ATPase, but did not. In addition, the cytotoxic did not affect glucose uptake in human cancer cells, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243443PMC
March 2020

Wheldone: Characterization of a Unique Scaffold from the Coculture of and .

Org Lett 2020 03 25;22(5):1878-1882. Epub 2020 Feb 25.

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.

Wheldone () was isolated and elucidated from a coculture of (NRRL 181) and (G536), where secondary metabolite biosynthesis was stimulated by antagonism between these fungi. First observed via analysis between these competing fungal cultures, the conditions were scaled to reproducibly generate , whose novel structure was elucidated by one- and two-dimensional NMR and mass spectrometry. Compound displayed cytotoxic activity against breast, ovarian, and melanoma cancer cell lines.
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http://dx.doi.org/10.1021/acs.orglett.0c00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153779PMC
March 2020

Fallopian tube initiation of high grade serous ovarian cancer and ovarian metastasis: Mechanisms and therapeutic implications.

Cancer Lett 2020 04 15;476:152-160. Epub 2020 Feb 15.

Department of Animal Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA. Electronic address:

Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention.
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http://dx.doi.org/10.1016/j.canlet.2020.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069002PMC
April 2020

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

Bioorg Med Chem 2020 02 7;28(4):115301. Epub 2020 Jan 7.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States. Electronic address:

A new non-cytotoxic [(+)-17β-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na/K-ATPase. Compound 3 docks deeply in the Na/K-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na/K-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na/K-ATPase. Thus, 3 was found to inhibit Na/K-ATPase, but 1 did not. In addition, the cytotoxic and Na/K-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na/K-ATPase but not by interacting with glucose transporters.
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http://dx.doi.org/10.1016/j.bmc.2019.115301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029422PMC
February 2020

Verticillin A Causes Apoptosis and Reduces Tumor Burden in High-Grade Serous Ovarian Cancer by Inducing DNA Damage.

Mol Cancer Ther 2020 01;19(1):89-100

Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy in women worldwide and the fifth most common cause of cancer-related deaths among U.S. women. New therapies are needed to treat HGSOC, particularly because most patients develop resistance to current first-line therapies. Many natural product and fungal metabolites exhibit anticancer activity and represent an untapped reservoir of potential new agents with unique mechanism(s) of action. Verticillin A, an epipolythiodioxopiperazine alkaloid, is one such compound, and our recent advances in fermentation and isolation are now enabling evaluation of its anticancer activity. Verticillin A demonstrated cytotoxicity in HGSOC cell lines in a dose-dependent manner with a low nmol/L IC Furthermore, treatment with verticillin A induced DNA damage and caused apoptosis in HGSOC cell lines OVCAR4 and OVCAR8. RNA-Seq analysis of verticillin A-treated OVCAR8 cells revealed an enrichment of transcripts in the apoptosis signaling and the oxidative stress response pathways. Mass spectrometry histone profiling confirmed reports that verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. To facilitate delivery of verticillin A and to monitor its ability to reduce HGSOC tumor burden, verticillin A was encapsulated into an expansile nanoparticle (verticillin A-eNP) delivery system. In an human ovarian cancer xenograft model, verticillin A-eNPs decreased tumor growth and exhibited reduced liver toxicity compared with verticillin A administered alone. This study confirmed that verticillin A has therapeutic potential for treatment of HGSOC and that encapsulation into expansile nanoparticles reduced liver toxicity.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951445PMC
January 2020

Detection of Ovarian Cancer Using Samples Sourced from the Vaginal Microenvironment.

J Proteome Res 2020 01 2;19(1):503-510. Epub 2019 Dec 2.

Department of Pharmaceutical Sciences , University of Illinois at Chicago , 833 S Wood Street , Chicago , Illinois 60612 , United States.

Mass spectrometry (MS) offers high levels of specificity and sensitivity in clinical applications, and we have previously been able to demonstrate that matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS is capable of distinguishing two-component cell mixtures at low limits of detection. Ovarian cancer is notoriously difficult to detect due to the lack of diagnostic techniques available to the medical community. By sampling a local microenvironment, such as the vaginal canal and cervix, a MS based method is presented for monitoring disease progression from proximal samples to the diseased tissue. A murine xenograft model of high grade serous ovarian carcinoma (HGSOC) was used for this study, and vaginal lavages were obtained from mice on a weekly basis throughout disease progression and subjected to our MALDI-TOF MS workflow followed by statistical analyses. Proteins in the 4-20 kDa region of the mass spectrum yielded a fingerprint that we could consistently measure over time that correlated with disease progression. These fingerprints were found to be largely stable across all mice, with the protein fingerprint converging toward the end point of the study. MALDI-TOF MS serves as a unique analytical technique for measuring a sampled vaginal microenvironment in a specific and sensitive manner for the detection of HGSOC in a murine model.
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http://dx.doi.org/10.1021/acs.jproteome.9b00694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020100PMC
January 2020

Engineering Fluorine into Verticillins (Epipolythiodioxopiperazine Alkaloids) via Precursor-Directed Biosynthesis.

J Nat Prod 2019 11 21;82(11):3104-3110. Epub 2019 Oct 21.

Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , North Carolina 27402 , United States.

Precursor-directed biosynthesis was used to generate a series of fluorinated verticillins. The biosynthesis of these epipolythiodioxopiperazine alkaloids was monitored via the droplet liquid microjunction surface sampling probe (droplet probe), and a suite of NMR and mass spectrometry data were used for their characterization. All analogues demonstrated nanomolar IC values vs a panel of cancer cell lines. This approach yielded new compounds that would be difficult to generate via synthesis.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996222PMC
November 2019

Structurally Modified Cyclopenta[]benzofuran Analogues Isolated from .

J Nat Prod 2019 10 17;82(10):2870-2877. Epub 2019 Oct 17.

Institute of Ecology and Biological Resources , Vietnamese Academy of Science and Technology , Hanoi , Vietnam.

Four new cyclopenta[]benzofuran derivatives based on an unprecedented carbon skeleton (-), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue () of 5‴-episilvestrol (episilvestrol, ), were isolated from an aqueous extract of a large-scale re-collection of the roots of collected in Vietnam. Compound demonstrated mutarotation in solution due to the presence of a hydroxy group at C-2‴, leading to the isolation of a racemic mixture, despite being purified on a chiral-phase HPLC column. Silvestrol () and episilvestrol () were isolated from the most potently cytotoxic chloroform subfraction of the roots. All new structures were elucidated using 1D and 2D NMR, HRESIMS, IR, UV, and ECD spectroscopic data. Of the five newly isolated compounds, only compound exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC values of 2.3 μM in both cases. The isolated compounds (-) double the number of dioxanyl ring-containing rocaglate analogues reported to date from species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819999PMC
October 2019

Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated With Polycystic Ovarian Syndrome.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US.

Context: Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer.

Objective: To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established.

Design: Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing.

Setting: Academic institution.

Patients: Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent.

Main Outcome Measures: Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured.

Results: A method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids.

Conclusions: A new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.
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http://dx.doi.org/10.1210/clinem/dgz100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112974PMC
March 2020

Water-Soluble Nanoconjugate for Enhanced Cellular Delivery of Receptor-Targeted Magnetic Resonance Contrast Agents.

Bioconjug Chem 2019 11 22;30(11):2947-2957. Epub 2019 Oct 22.

Department of Biomedical Engineering, Feinberg School of Medicine , Northwestern University , Chicago , Illinois 60611 , United States.

ProGlo is an efficient steroid receptor-targeted magnetic resonance (MR) imaging contrast agent (CA). It has been shown to bind to the progesterone receptor (PR) and produce enhanced image contrast in PR-positive cells and tissues and . However, the hydrophobicity of the steroid targeting domain of ProGlo (logP = 1.4) limits its formulation and delivery at clinically relevant doses. In this work, a hydrophobic moiety was utilized to drive efficient adsorption onto nanodiamond (ND) clusters to form a water-soluble nanoconstruct (logP = -2.4) with 80% release in 8 h under biological conditions. In cell culture, the ND-ProGlo construct delivered increased concentrations of ProGlo to target cells compared to ProGlo alone. Importantly, these results were accomplished without the use of solvents such as DMSO, providing a significant advance toward formulating ProGlo for translational applications. Biodistribution studies confirm the delivery of ProGlo to PR(+) tissues with enhanced efficacy over untargeted controls. These results demonstrate the potential for a noncovalent ND-CA construct as a general strategy for solubilizing and delivering hydrophobic targeted MR CAs.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868311PMC
November 2019

Proteomic analysis reveals a role for PAX8 in peritoneal colonization of high grade serous ovarian cancer that can be targeted with micelle encapsulated thiostrepton.

Oncogene 2019 08 11;38(32):6003-6016. Epub 2019 Jul 11.

Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.

High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women yet effective targeted therapies against this disease are limited. The heterogeneity of HGSOC, including few shared oncogenic drivers and origination from both the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE), has hampered development of targeted drug therapies. PAX8 is a lineage-specific transcription factor expressed in the FTE that is also ubiquitously expressed in HGSOC where it is an important driver of proliferation, migration, and cell survival. PAX8 is not normally expressed in the OSE, but it is turned on after malignant transformation. In this study, we use proteomic and transcriptomic analysis to examine the role of PAX8 leading to increased migratory capabilities in a human ovarian cancer model, as well as in tumor models derived from the OSE and FTE. We find that PAX8 is a master regulator of migration with unique downstream transcriptional targets that are dependent on the cell's site of origin. Importantly, we show that targeting PAX8, either through CRISPR genomic alteration or through drug treatment with micelle encapsulated thiostrepton, leads to a reduction in tumor burden. These findings suggest PAX8 is a unifying protein driving metastasis in ovarian tumors that could be developed as an effective drug target to treat HGSOC derived from both the OSE and FTE.
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http://dx.doi.org/10.1038/s41388-019-0842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687548PMC
August 2019

Reduced PAX2 expression in murine fallopian tube cells enhances estrogen receptor signaling.

Carcinogenesis 2020 07;41(5):646-655

Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL, USA.

High-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.
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http://dx.doi.org/10.1093/carcin/bgz127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350556PMC
July 2020

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary.

Cancers (Basel) 2019 Jun 25;11(6). Epub 2019 Jun 25.

Department of Pharmaceutical Sciences, Center for Biomolecular Science, University of Illinois at Chicago, Chicago, IL 60607, USA.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8 PTEN mice. MOE PTEN cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTEN cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.
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http://dx.doi.org/10.3390/cancers11060884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627669PMC
June 2019