Publications by authors named "Steven M Swanson"

100 Publications

Mammary Tumors Growing in the Absence of Growth Hormone Are More Sensitive to Doxorubicin Than Wild-Type Tumors.

Endocrinology 2021 Apr;162(4)

School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA.

Previously, we reported that N-methyl-N-nitrosourea (MNU)-induced mammary tumors could be established in mutant spontaneous dwarf rats (SDRs), which lack endogenous growth hormone (GH) by supplementing with exogenous GH, and almost all such tumors regressed upon GH withdrawal. When the highly inbred SDR line was outcrossed to wild-type (WT) Sprague-Dawley rats, MNU-induced mammary tumors could still be established in resulting outbred SDRs by supplementing with exogenous GH. However, unlike tumors in inbred SDRs, 65% of mammary tumors established in outbred SDRs continued growth after GH withdrawal. We further tested whether these tumors were more sensitive to doxorubicin than their WT counterparts. To accomplish this, MNU-induced mammary tumors were established in WT rats and in SDRs supplemented with exogenous GH. Once mammary tumors reached 1 cm3 in size, exogenous GH was withdrawn from SDRs, and the subset that harbored tumors that continued or resumed growth in the absence of GH were selected for doxorubicin treatment. Doxorubicin was then administered in 6 injections over 2 weeks at 2.5 mg/kg or 1.25 mg/kg for both the WT and SDR groups. The SDR mammary tumors that had been growing in the absence of GH regressed at both doxorubicin doses while WT tumors continued to grow robustly. The regression of SDR mammary tumors treated with 1.25 mg/kg doxorubicin was accompanied by reduced proliferation and dramatically higher apoptosis relative to the WT mammary tumors treated with 1.25 mg/kg doxorubicin. These data suggest that downregulating GH signaling may decrease the doxorubicin dose necessary to effectively treat breast cancer.
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http://dx.doi.org/10.1210/endocr/bqab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881836PMC
April 2021

Prostate epithelial-specific expression of activated PI3K drives stromal collagen production and accumulation.

J Pathol 2020 02 28;250(2):231-242. Epub 2019 Nov 28.

Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI, USA.

We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation (Pbsn-cre4Prb;PI3K ). We hypothesized that direct activation would cause rapid neoplasia and cancer progression. Pbsn-cre4Prb;PI3K mice developed widespread prostate intraepithelial hyperplasia, but stromal invasion was limited and overall progression was slower than anticipated. However, the model produced profound and progressive stromal remodeling prior to explicit epithelial neoplasia. Increased stromal cellularity and inflammatory infiltrate were evident as early as 4 months of age and progressively increased through 12 months of age, the terminal endpoint of this study. Prostatic collagen density and phosphorylated SMAD2-positive prostatic stromal cells were expansive and accumulated with age, consistent with pro-fibrotic TGF-β pathway activation. Few reported mouse models accumulate prostate-specific collagen to the degree observed in Pbsn-cre4Prb;PI3K . Our results indicate a signaling process beginning with prostatic epithelial PI3K and TGF-β signaling that drives prostatic stromal hypertrophy and collagen accumulation. These mice afford a unique opportunity to explore molecular mechanisms of prostatic collagen accumulation that is relevant to cancer progression, metastasis, inflammation and urinary dysfunction. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071816PMC
February 2020

The role of WNT10B in normal prostate gland development and prostate cancer.

Prostate 2019 10 21;79(14):1692-1704. Epub 2019 Aug 21.

Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.

Background: WNT signaling is implicated in embryonic development, and in adult tissue homeostasis, while its deregulation is evident in disease. This study investigates the unique roles of canonical WNT10B in both normal prostate development and prostate cancer (PCa) progression.

Methods: Organ culture and rat ventral prostates (VPs) were used to study Wnt10b ontogeny and growth effect of WNT10B protein. PB-SV40 LTag rat VPs were utilized for Wnt expression polymerase chain reaction (PCR) array and immunohistochemistry. Human localized PCa tissue microarrays (TMAs) were investigated for differential WNT10B expression. Human RNA-seq data sets were queried for differential expression of WNT10B in metastatic and localized PCa. Knockdown of WNT10B in PC3 cells was utilized to study its effects on proliferation, stemness, epithelial to mesenchymal transition (EMT), and xenograft propagation.

Results: Wnt10b expression was highest at birth and rapidly declined in the postnatal rat VP. Exogenous WNT10B addition to culture developing VPs decreased growth suggesting an antiproliferative role. VPs from PB-SV40 LTag rats with localized PCa showed a 25-fold reduction in Wnt10b messenger RNA (mRNA) expession, confirmed at the protein level. Human PCa TMAs revealed elevated WNT10B protein in prostate intraepithelial neoplasia compared with normal prostates but reduced levels in localized PCa specimens. In contrast, RNA-seq data set of annotated human PCa metastasis found a significant increase in WNT10B mRNA expression compared with localized tumors suggesting stage-specific functions of WNT10B. Similarly, WNT10B mRNA levels were increased in metastatic cell lines PC3, PC3M, as well as in HuSLC, a PCa stem-like cell line, as compared with disease-free primary prostate epithelial cells. WNT10B knockdown in PC3 cells reduced expression of EMT genes, MMP9 and stemness genes NANOG and SOX2 and markedly reduced the stem cell-like side population. Furthermore, loss of WNT10B abrogated the ability of PC3 cells to propagate tumors via serial transplantation.

Conclusions: Taken together, these results suggest a dual role for WNT10B in normal development and in PCa progression with opposing functions depending on disease stage. We propose that decreased WNT10B levels in localized cancer allow for a hyperproliferative state, whereas increased levels in advanced disease confer a stemness and malignant propensity which is mitigated by knocking down WNT10B levels. This raises the potential for WNT10B as a novel target for therapeutic intervention in metastatic PCa.
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http://dx.doi.org/10.1002/pros.23894DOI Listing
October 2019

Potential Anticancer Agents Characterized from Selected Tropical Plants.

J Nat Prod 2019 03 4;82(3):657-679. Epub 2019 Mar 4.

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

Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant secondary metabolites as additional cancer chemotherapeutic lead compounds. In the present review, progress on the discovery of plant-derived compounds of the biflavonoid, lignan, sesquiterpene, steroid, and xanthone structural types is presented. Several potential anticancer leads of these types have been characterized from tropical plants collected in three countries as part of our ongoing collaborative multi-institutional project. Preliminary structure-activity relationships and work on in vivo testing and cellular mechanisms of action are also discussed. In addition, the relevant work reported by other groups on the same compound classes is included herein.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441492PMC
March 2019

Biochemical and Anti-Triple Negative Metastatic Breast Tumor Cell Properties of Psammaplins.

Mar Drugs 2018 Nov 10;16(11). Epub 2018 Nov 10.

Institute of Interdisciplinary Integrative Medical Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New District, Shanghai 201203, China.

Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massagué and colleagues isolated organotropic subclones and established organ-specific gene signatures associated with lung-, bone-, and brain-specific metastatic triple-negative breast cancer (TNBC) MDA-MB-231 cells. Using these genetically characterized metastatic subclones specific to lung (LM4175), bone (BoM1833), and brain (BrM-2a), we evaluated marine natural products for the ability to differentially suppress metastatic breast cancer cells in a target organ-dependent manner. Psammaplin-based histone deacetylase (HDAC) inhibitors were found to differentially inhibit HDAC activity, induce activation of hypoxia-inducible factor-1 (HIF-1), and disrupt organotropic metastatic TNBC subclone growth. Further, psammaplins distinctly suppressed the outgrowth of BoM1833 tumor spheroids in 3D-culture systems. Similar results were observed with the prototypical HDAC inhibitor trichostatin A (TSA). These organotropic tumor cell-based studies suggest the potential application of HDAC inhibitors that may yield new directions for anti-metastatic breast tumor research and drug discovery.
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http://dx.doi.org/10.3390/md16110442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265740PMC
November 2018

Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition.

Mol Cancer Ther 2018 10 17;17(10):2123-2135. Epub 2018 Jul 17.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.

High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition may be required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single agent against HGSOC This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian cancer. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168422PMC
October 2018

Special Issue in Honor of Professor Susan Band Horwitz.

J Nat Prod 2018 03;81(3):449-450

Research Triangle Institute , Research Triangle Park , North Carolina , United States.

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http://dx.doi.org/10.1021/acs.jnatprod.8b00098DOI Listing
March 2018

Ribocyclophanes A-E, Glycosylated Cyclophanes with Antiproliferative Activity from Two Cultured Terrestrial Cyanobacteria.

J Nat Prod 2018 03 30;81(3):572-578. Epub 2018 Jan 30.

Department of Medicinal Chemistry and Pharmacognosy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.

The cell extracts of two cultured freshwater Nostoc spp., UIC 10279 and UIC 10366, both from the suburbs of Chicago, showed antiproliferative activity against MDA-MB-231 and MDA-MB-435 cancer cell lines. Bioassay-guided fractionation led to the isolation of five glycosylated cylindrocyclophanes, named ribocyclophanes A-E (1-5) and cylindrocyclophane D (6). The structure determination was carried out by HRESIMS and 1D and 2D NMR analyses and confirmed by single-crystal X-ray crystallography. The structures of ribocyclophanes A-E (1-5) contain a β-d-ribopyranose glycone in the rare C conformation. Among isolated compounds, ribocyclophane D (4) showed antiproliferative activity against MDA-MB-435 and MDA-MB-231 cancer cells with an IC value of less than 1 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898370PMC
March 2018

(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks.

J Nat Prod 2017 03 24;80(3):659-669. Epub 2017 Feb 24.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na/K-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768141PMC
March 2017

Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity.

J Nat Prod 2017 03 16;80(3):648-658. Epub 2016 Dec 16.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365359PMC
March 2017

Discovery of Anticancer Agents of Diverse Natural Origin.

Anticancer Res 2016 11;36(11):5623-5637

Eisai Inc., Andover, MA, U.S.A.

Recent progress is described in an ongoing collaborative multidisciplinary research project directed towards the purification, structural characterization, chemical modification, and biological evaluation of new potential natural product anticancer agents obtained from a diverse group of organisms, comprising tropical plants, aquatic and terrestrial cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which initial extracts, chromatographic fractions, and purified isolated compounds of these acquisitions are tested. Several promising biologically active lead compounds from each major organism class investigated are described, and these may be seen to be representative of a very wide chemical diversity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098703PMC
http://dx.doi.org/10.21873/anticanres.11146DOI Listing
November 2016

Di-nor- and 17-nor-pimaranes from Icacina trichantha.

J Nat Prod 2016 07 24;79(7):1815-21. Epub 2016 Jun 24.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

Six new pimarane derivatives, including two di-nor-pimaranes (1, 2), two 17-nor-pimaranes (3, 4), and two 17-nor-(9β-H)-pimaranes (5, 6), were isolated from the tuber of Icacina trichantha. Their structures were elucidated based on spectroscopic and HRMS data. The absolute configurations of 1 and 5 were determined by single-crystal X-ray diffraction, and that of 2 was established by electronic circular dichroism data analysis. Compound 3 possesses a unique C-20 acetal moiety. This is the first report of the isolation of di-nor-(9β-H)-pimarane derivatives from Icacina plants. Compounds 5 and 6 showed moderate cytotoxicity against MDA-MB-435, MDA-MB-231, and OVCAR3 cell lines, with IC50 values of 2.91-7.60 and 1.48-3.23 μM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096845PMC
July 2016

Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases.

PLoS One 2016 12;11(5):e0155262. Epub 2016 May 12.

Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in human patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865188PMC
July 2017

Silvestrol induces early autophagy and apoptosis in human melanoma cells.

BMC Cancer 2016 Jan 13;16:17. Epub 2016 Jan 13.

Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, 60607, USA.

Background: Silvestrol is a cyclopenta[b]benzofuran that was isolated from the fruits and twigs of Aglaia foveolata, a plant indigenous to Borneo in Southeast Asia. The purpose of the current study was to determine if inhibition of protein synthesis caused by silvestrol triggers autophagy and apoptosis in cultured human cancer cells derived from solid tumors.

Methods: In vitro cell viability, flow cytometry, fluorescence microscopy, qPCR and immunoblot was used to study the mechanism of action of silvestrol in MDA-MB-435 melanoma cells.

Results: By 24 h, a decrease in cyclin B and cyclin D expression was observed in silvestrol-treated cells relative to control. In addition, silvestrol blocked progression through the cell cycle at the G2-phase. In silvestrol-treated cells, DAPI staining of nuclear chromatin displayed nucleosomal fragments. Annexin V staining demonstrated an increase in apoptotic cells after silvestrol treatment. Silvestrol induced caspase-3 activation and apoptotic cell death in a time- and dose-dependent manner. Furthermore, both silvestrol and SAHA enhanced autophagosome formation in MDA-MB-435 cells. MDA-MB-435 cells responded to silvestrol treatment with accumulation of LC3-II and time-dependent p62 degradation. Bafilomycin A, an autophagy inhibitor, resulted in the accumulation of LC3 in cells treated with silvestrol. Silvestrol-mediated cell death was attenuated in ATG7-null mouse embryonic fibroblasts (MEFs) lacking a functional autophagy protein.

Conclusions: Silvestrol potently inhibits cell growth and induces cell death in human melanoma cells through induction of early autophagy and caspase-mediated apoptosis. Silvestrol represents a natural product scaffold that exhibits potent cytotoxic activity and could be used for the further study of autophagy and its relationship to apoptosis in cancer cells.
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http://dx.doi.org/10.1186/s12885-015-1988-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712514PMC
January 2016

(9βH)-Pimaranes and Derivatives from the Tuber of Icacina trichantha.

J Nat Prod 2015 Nov 2;78(11):2731-7. Epub 2015 Nov 2.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.

New 17-nor-pimaranes (1, 2), (9βH)-pimaranes (3, 4), and 17-nor-(9βH)-pimarane (5) were isolated from the tuber of Icacina trichantha. The structures were elucidated based on spectroscopic and HRMS data. The absolute configurations of 3 and 5 were determined by single-crystal X-ray diffraction. Compound 5 possesses a unique 19,20-δ-lactone moiety. Compound 3 showed cytotoxicity against MDA-MB-435 (human melanoma cancer) cells with an IC50 value of 7.04 μM. A plausible biogenetic pathway for compounds 1-5 is proposed.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703074PMC
November 2015

Cytotoxic Homoisoflavones from the Bulbs of Bellevalia eigii.

J Nat Prod 2015 Jul 6;78(7):1708-15. Epub 2015 Jul 6.

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

Eight new and 10 known compounds were isolated from an organic extract of the bulbs of Bellevalia eigii as part of a search for anticancer leads from native plants of Jordan. Of these, the series of 16 homoisoflavonoids (1-16) comprise the seven new analogues 7-O-methyl-3'-hydroxy-3,9-dihydropunctatin (3), 6-hydroxy-7-O-methyl-3,9-dihydropunctatin (6), 7,4'-di-O-methyl-3'-hydroxy-3,9-dihydropunctatin (9), 7-O-methylpunctatin (10), 7-O-methyl-3'-hydroxypunctatin (13), 5-hydroxy-7,8-dimethoxychroman-4-one (14), and 7-O-methyl-8-demethoxy-3-hydroxy-3,9-dihydropunctatin (15). The known ferulic acid-derived acrylamide (17) and the new methylthioacrylate bellegimycin (18) are also reported. The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 1-9, 15, and 16 were determined using ECD spectroscopy, while a modified Mosher's ester method was used for compound 18. Optical rotation data for the known compounds 1, 2, and 8 are reported here for the first time. The cytotoxic activities of all compounds were evaluated using the MDA-MB-435 (melanoma) and HT-29 (colon) cancer cell lines. Compounds 4 and 9 were the most potent on the latter cell line, with IC50 values of 1.0 and 1.1 μM, respectively. Compounds 1-18 were assessed for antimicrobial activity using a collection of bacteria and fungi; compounds 4 and 12 showed promising activity against the bacterium Mycobacterium smegmatis with MIC values of 17 and 24 μg/mL, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615712PMC
July 2015

New diketopiperazine dimer from a filamentous fungal isolate of Aspergillus sydowii.

Magn Reson Chem 2015 Aug 3;53(8):616-9. Epub 2015 Jun 3.

Department of Chemistry Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC, 27402, United States.

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http://dx.doi.org/10.1002/mrc.4254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692248PMC
August 2015

Trichormamides C and D, antiproliferative cyclic lipopeptides from the cultured freshwater cyanobacterium cf. Oscillatoria sp. UIC 10045.

Bioorg Med Chem 2015 Jul 1;23(13):3153-62. Epub 2015 May 1.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, United States. Electronic address:

Extract from the cultured freshwater cf. Oscillatoria sp. UIC 10045 showed antiproliferative activity against HT-29 cell line. Bioassay-guided fractionation led to the isolation of two new cyclic lipopeptides, named trichormamides C (1) and D (2). The planar structures were determined by combined analyses of HRESIMS, Q-TOF ESIMS/MS, and 1D and 2D NMR spectra. The absolute configurations of the amino acid residues were assigned by advanced Marfey's analysis after partial and complete acid hydrolysis. Trichormamides C (1) is a cyclic undecapeptide and D (2) is a cyclic dodecapeptide, both containing a lipophilic β-aminodecanoic acid residue. Trichormamide C (1) displayed antiproliferative activities against HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 1.7 and 1.0μM, respectively, as well as anti-Mycobacterium tuberculosis activity with MIC value of 23.8μg/mL (17.3μM). Trichormamide D (2) was found to be less potent against both HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 11.5 and 11.7μM, respectively.
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http://dx.doi.org/10.1016/j.bmc.2015.04.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469202PMC
July 2015

17-Norpimaranes and (9βH)-17-Norpimaranes from the Tuber of Icacina trichantha.

J Nat Prod 2015 Apr 17;78(4):789-96. Epub 2015 Mar 17.

†Department of Medicinal Chemistry and Pharmacognosy and WHO Collaborating Center for Traditional Medicine, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.

Seven new 17-norpimarane and (9βH)-17-norpimarane diterpenoids, icacinlactones A-G (1-7), were isolated from the tuber of Icacina trichantha. The structures were elucidated by spectroscopic and HRMS techniques, and the absolute configuration of 2 was determined by means of X-ray crystallographic analysis. Compounds 1-7, as well as four known related structures, were evaluated for cytotoxic activity against MDA-MB-435 (human melanoma cancer), MDA-MB-231 (human breast cancer), and OVCAR3 (human ovarian cancer) cell lines. Several of these natural products displayed significant cytotoxic activity, with humirianthenolide C being the most active.
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http://dx.doi.org/10.1021/np5010328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703125PMC
April 2015

Biosynthetically Distinct Cytotoxic Polyketides from

European J Org Chem 2015 Jan;2015(1):109-121

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, United States, Homepage: http://www.uncg.edu/che/Group_Research_Page/NicholasOberlies.

Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture (MSX45109) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B (), blennolide H (), 11-deoxy blennolide D (), blennolide I (), blennolide J (), and pyrenomycin (). The known compounds were: secalonic acid A (), secalonic acid E (), secalonic acid G (), penicillixanthone A (), paecilin B (), aigialomycin A (), hypothemycin (), dihydrohypothemycin (), pyrenochaetic acid C (), and nidulalin B (). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds - were determined using ECD spectroscopy combined with time-dependent density functional theory (TDDFT) calculations, while a modified Mosher's ester method was used for compound . The cytotoxic activities of compounds (-) were evaluated using the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compounds , , and were the most potent with IC values ranging from 0.16 to 2.14 μM. When tested against a panel of bacteria and fungi, compounds and showed promising activity against the Gram-positive bacterium with MIC values of 5 and 15 μg/mL, respectively.
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http://dx.doi.org/10.1002/ejoc.201402984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283843PMC
January 2015

Cytotoxic (9βH)-pimarane and (9βH)-17-norpimarane diterpenes from the tuber of Icacina trichantha.

Chem Biodivers 2014 Dec;11(12):1914-22

Department of Medicinal Chemistry and Pharmacognosy, WHO Collaborating Center for Traditional Medicine, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA, (phone: +1-312-996-1557; fax: +1-312-996-7107); Department of Veterinary Physiology and Pharmacology, Faculty of Veterinary Medicine, University of Nigeria, Nsukka, Nigeria; Department of Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Abuja, PMB 117, Abuja, Nigeria.

Three (9βH)-pimaranes, 1, 2, and 3, and two (9βH)-17-norpimaranes, 4 and 5, belonging to a rare compound class in nature, were obtained from the tubers of Icacina trichantha for the first time. Compound 1 is a new natural product, and 2-5 have been previously reported. The structures were elucidated based on NMR and MS data, and optical rotation values. The absolute configurations of (9βH)-pimaranes were unambiguously established based on X-ray crystallographic analysis. Full NMR signal assignments for the known compounds 2, 4, and 5, which were not available in previous publications, are also reported. All five isolates displayed cytotoxic activities on MDA-MB-435 cells (IC50 0.66-6.44 μM), while 2, 3, and 4 also exhibited cytotoxicities on HT-29 cells (IC50 3.00-4.94 μM).
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http://dx.doi.org/10.1002/cbdv.201400151DOI Listing
December 2014

Investigation of Vietnamese plants for potential anticancer agents.

Phytochem Rev 2014 Dec;13(4):727-739

College of Pharmacy, The Ohio State University, 500 West 12 Avenue, Columbus, OH 43210, USA.

Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities.
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http://dx.doi.org/10.1007/s11101-014-9335-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225705PMC
December 2014

Sorbicillinoid analogs with cytotoxic and selective anti-Aspergillus activities from Scytalidium album.

J Antibiot (Tokyo) 2015 Mar 24;68(3):191-6. Epub 2014 Sep 24.

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

As part of an ongoing project to explore filamentous fungi for anticancer and antibiotic leads, 11 compounds were isolated and identified from an organic extract of the fungus Scytalidium album (MSX51631) using bioactivity-directed fractionation against human cancer cell lines. Of these, eight compounds were a series of sorbicillinoid analogs (1-8), of which four were new (scalbucillin A (2), scalbucillin B (3), scalbucillin C (6) and scalbucillin D (8)), two were phthalides (9-10) and one was naphthalenone (11). Compounds (1-11) were tested in the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compound 1 was the most potent with IC50 values of 1.5 and 0.5 μM, followed by compound 5 with IC50 values of 2.3 and 2.5 μM at 72 h. Compound 1 showed a 48-h IC50 value of 3.1 μM when tested against the lymphocytic leukemia cell line OSU-CLL, while the nearly identical compound 5 had almost no activity in this assay. Compounds 1 and 5 showed selective and equipotent activity against Aspergillus niger with minimum IC values of 0.05 and 0.04 μg ml(-1) (0.20 and 0.16 μM), respectively. The in vitro hemolytic activity against sheep erythrocytes of compounds 1 and 5 was investigated and were found to provoke 10% hemolysis at 52.5 and 45.0 μg ml(-1), respectively, indicative of a promising safety factor.
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http://dx.doi.org/10.1038/ja.2014.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372511PMC
March 2015

Carbamidocyclophanes F and G with Anti- Activity from the Cultured Freshwater Cyanobacterium sp.

Tetrahedron Lett 2014 Jan;55(3):686-689

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612.

Two new ( and ) and three known () carbamidocyclophanes were isolated from a cultured freshwater cyanobacterium sp. (UIC 10274) obtained from a sample collected at Des Plaines, Illinois. Their planar structures and stereoconfigurations were determined by extensive spectroscopic analysis including 1D/2D NMR experiments, HRESIMS as well as CD spectroscopy. Carbamidocyclophane F () showed potent anti- activity in the microplate Alamar blue assay and low-oxygen-recovery assay with MIC values of 0.8 and 5.4 µM, respectively. Carbamidocyclophane F () also displayed antimicrobial activities against the gram positive bacteria and with MIC values of 0.1 and 0.2 µM, respectively. Carbamidocyclophane F () and Carbamidocyclophane G () both showed antiproliferative activity against MDA-MB-435 and HT-29 human cancer cell lines with IC values in the range from 0.5 to 0.7 µM.
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http://dx.doi.org/10.1016/j.tetlet.2013.11.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161986PMC
January 2014

Greensporones: resorcylic acid lactones from an aquatic Halenospora sp.

J Nat Prod 2014 Sep 5;77(9):2088-98. Epub 2014 Aug 5.

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

Fourteen new resorcylic acid lactones (1-14) were isolated from an organic extract of a culture of a freshwater aquatic fungus Halenospora sp. originating from a stream in North Carolina. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configuration of one representative member of the compounds (7) was assigned using X-ray crystallography of an analogue that incorporated a heavy atom, whereas for compounds 8-11, a modified Mosher's ester method was utilized. The relative configurations of compounds 12-14 were determined on the basis of NOE data. Compounds 12-14 were proposed as artifacts produced by intramolecular cycloetherification of the ε-hydroxy-α,β-unsaturated ketone moieties of the parent compounds during the purification processes. The isolated compounds, except for 8 and 12, were tested against the MDA-MB-435 (melanoma) and HT-29 (colon) cancer cell lines. Compound 5 was the most potent, with IC50 values of 2.9 and 7.5 μM, respectively. The compounds were evaluated as TAK1-TAB1 inhibitors but were found to be inactive.
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http://dx.doi.org/10.1021/np500497rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176394PMC
September 2014

Trichormamides A and B with Antiproliferative Activity from the Cultured Freshwater Cyanobacterium Trichormus sp. UIC 10339.

J Nat Prod 2014 Aug 4;77(8):1871-80. Epub 2014 Aug 4.

†Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, Illinois 60612, United States.

Two new cyclic lipopeptides, trichormamides A (1) and B (2), were isolated from the cultured freshwater cyanobacterium Trichormus sp. UIC 10339. The strain was obtained from a sample collected in Raven Lake in Northern Wisconsin. The planar structures of trichormamides A (1) and B (2) were determined using a combination of spectroscopic analyses including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the amino acid residues were assigned by the advanced Marfey's method after acid hydrolysis. Trichormamide A (1) is a cyclic undecapeptide containing two D-amino acid residues (D-Tyr and D-Leu) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) is a cyclic dodecapeptide characterized by the presence of four nonstandard α-amino acid residues (homoserine, N-methylisoleucine, and two 3-hydroxyleucines) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) was cytotoxic against MDA-MB-435 and HT-29 cancer cell lines with IC50 values of 0.8 and 1.5 μM, respectively.
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http://dx.doi.org/10.1021/np5003548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143178PMC
August 2014

Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.

Carcinogenesis 2014 Nov 1;35(11):2467-73. Epub 2014 Aug 1.

Research and Development Division, Jesse Brown Veteran Affairs Medical Center, 820 S. Damen Ave, Bldg. 11A, Suite 6215, MP151, Chicago, IL 60612, USA, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA,

Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status.
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http://dx.doi.org/10.1093/carcin/bgu161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216054PMC
November 2014

Assay development for the discovery of semaphorin 3B inducing agents from natural product sources.

Fitoterapia 2014 Oct 10;98:184-91. Epub 2014 Jul 10.

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

Semaphorins are a class of membrane-bound and secreted proteins. They have been found to regulate basic cell functions such as axonal growth cone guidance and recent studies have focused on their effect on tumor progression. Semaphorin 3B (Sema3B) particularly is a secreted protein that has been known to modulate proliferation and apoptosis, processes that are critical for tumor progression and development. In spite of its importance, there is yet no high-throughput screening assay available to detect or quantify the expression of Sema3B for natural product anticancer drug discovery purposes. Therefore, the development of a new high-throughput bioassay for the discovery of Sema3B inducing agents from natural product sources is described herein. A wide variety of pure compounds and extracts from plants and microorganisms has been found suitable for screening using this Sema3B assay to detect and quantify the effect of Sema3B inducing agents and thereby identify new selective bioactive Sema3B lead compounds for anticancer drug discovery and development. Also, this new bioassay procedure is based on a high-throughput platform using an enzyme-linked immunosorbent assay that involves the optimization of sensitivity and selectivity levels as well as accuracy, reproducibility, robustness, and cost effectiveness.
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http://dx.doi.org/10.1016/j.fitote.2014.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196688PMC
October 2014

Epigenetic Manipulation of a Filamentous Fungus by the Proteasome-Inhibitor Bortezomib Induces the Production of an Additional Secondary Metabolite.

RSC Adv 2014 Jan;4(35):18329-18335

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, North Carolina 27402, United States.

The use of epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, has been explored increasingly as a technique to induce the production of additional microbial secondary metabolites. The application of such molecules to microbial cultures has been shown to upregulate otherwise suppressed genes, and in several cases has led to the production of new molecular structures. In this study, the proteasome inhibitor bortezomib was used to induce the production of an additional metabolite from a filamentous fungus (Pleosporales). The induced metabolite was previously isolated from a plant, but the configuration was not assigned until now; in addition, an analogue was isolated from a degraded sample, yielding a new compound. Proteasome inhibitors have not previously been used in this application and offer an additional tool for microbial genome mining.
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http://dx.doi.org/10.1039/C4RA00274ADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061710PMC
January 2014