Publications by authors named "Kimberly Heath"

3 Publications

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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

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

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