Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines

Christopher R Bodle; Duncan I Mackie; Michael P Hayes; Josephine H Schamp; Michael R Miller; Michael D Henry; Jonathan A Doorn; Jon C D Houtman; Michael A James; David L Roman

doi:10.1021/acs.jnatprod.7b00112

Back

Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines

Journal article

Open access

Peer reviewed

Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines

Christopher R Bodle, Duncan I Mackie, Michael P Hayes, Josephine H Schamp, Michael R Miller, Michael D Henry, Jonathan A Doorn, Jon C D Houtman, Michael A James and David L Roman

Journal of natural products (Washington, D.C.), Vol.80(7), pp.1992-2000

07/28/2017

DOI: 10.1021/acs.jnatprod.7b00112

PMCID: PMC5567870

PMID: 28621943

Files and links (1)

url

http://doi.org/10.1021/acs.jnatprod.7b00112View

Open Access

Abstract

Regulator of G Protein Signaling (RGS) 17 is an overexpressed promoter of cancer survival in lung and prostate tumors, the knockdown of which results in decreased tumor cell proliferation in vitro. Identification of drug-like molecules inhibiting this protein could ameliorate the RGS17's pro-tumorigenic effect. Using high-throughput screening, a chemical library containing natural products was interrogated for inhibition of the RGS17-Gα interaction. Initial hits were verified in control and counter screens. Leads were characterized via biochemical, mass spectrometric, Western blot, microscopic, and cytotoxicity measures. Four known compounds (1-4) were identified with IC values ranging from high nanomolar to low micromolar. Three compounds were extensively characterized biologically, demonstrating cellular activity determined by confocal microscopy, and two compounds were assessed via ITC exhibiting high nanomolar to low micromolar dissociation constants. The compounds were found to have a cysteine-dependent mechanism of binding, verified through site-directed mutagenesis and cysteine reactivity assessment. Two compounds, sanguinarine (1) and celastrol (2), were found to be cytostatic against lung and prostate cancer cell lines and cytotoxic against prostate cancer cell lines in vitro, although the dependence of RGS17 on these phenomena remains elusive, a result that is perhaps not surprising given the multimodal cytostatic and cytotoxic activities of many natural products.

Lung Neoplasms - drug therapy

Cytostatic Agents - chemistry

GTP-Binding Protein Regulators - drug effects

Triterpenes - pharmacology

Humans

Male

Biological Products - pharmacology

Benzophenanthridines - pharmacology

Biological Products - chemistry

Cytotoxins - pharmacology

Isoquinolines - pharmacology

Cytotoxins - chemistry

Molecular Structure

Cytostatic Agents - pharmacology

Prostatic Neoplasms - drug therapy

Details

Title: Subtitle: Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines
Creators: Christopher R Bodle - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Duncan I Mackie - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Michael P Hayes - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Josephine H Schamp - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Michael R Miller - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Michael D Henry - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Jonathan A Doorn - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Jon C D Houtman - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Michael A James - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
David L Roman - Department of Surgery and □Pancreatic Cancer Program at the Medical College of Wisconsin, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, United States
Resource Type: Journal article
Publication Details: Journal of natural products (Washington, D.C.), Vol.80(7), pp.1992-2000
DOI: 10.1021/acs.jnatprod.7b00112
PMID: 28621943
PMCID: PMC5567870
NLM abbreviation: J Nat Prod
ISSN: 0163-3864
eISSN: 1520-6025
Publisher: United States
Grant note: R01 CA160470 / NCI NIH HHS T32 GM067795 / NIGMS NIH HHS P30 ES005605 / NIEHS NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA136729 / NCI NIH HHS T32 GM008365 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS S10 RR029274 / NCRR NIH HHS
Language: English
Date published: 07/28/2017
Academic Unit: Neurology; Pharmacy; Molecular Physiology and Biophysics; Microbiology and Immunology; Pathology; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Urology; Medicinal and Natural Products Chemistry; Internal Medicine
Record Identifier: 9984065498602771

Metrics

17 Record Views

24 Times Cited - Web of Science

See more details