Fluvastatin is effective against thymic carcinoma

Keitaro Hayashi; Yoshimasa Nakazato; Noriaki Morito; Mizuki Sagi; Tomoe Fujita; Naohiko Anzai; Masayuki Chida

doi:10.1016/j.lfs.2019.117110

Fluvastatin is effective against thymic carcinoma

Life Sci. 2020 Jan 1:240:117110. doi: 10.1016/j.lfs.2019.117110. Epub 2019 Nov 28.

Authors

Keitaro Hayashi¹, Yoshimasa Nakazato², Noriaki Morito³, Mizuki Sagi³, Tomoe Fujita³, Naohiko Anzai⁴, Masayuki Chida⁵

Affiliations

¹ Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Shimotsuga, Japan. Electronic address: khayashi@dokkyomed.ac.jp.
² Department of Diagnostic Pathology, Dokkyo Medical University School of Medicine, Shimotsuga, Japan.
³ Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Shimotsuga, Japan.
⁴ Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Shimotsuga, Japan; Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
⁵ Department of General Thoracic Surgery, Dokkyo Medical University School of Medicine, Shimotsuga, Japan.

PMID: 31786191
DOI: 10.1016/j.lfs.2019.117110

Abstract

Aims: Thymic carcinoma is a rare epithelial tumor, for which, optimal pharmacotherapeutic methods have not yet been established. To develop new drug treatments for thymic carcinoma, we investigated the effects of fluvastatin-mediated pharmacological inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) on thymic carcinoma.

Main methods: Thymic carcinoma tissue was surgically excised and HMGCR expression was assessed by immunohistochemistry. Ty82 human thymic carcinoma cells were treated with fluvastatin (1-10 μM) and their growth was monitored.

Key findings: HMGCR was expressed on carcinoma cells but not on normal epithelial cells in thymic tissue. Inhibition of HMGCR by fluvastatin suppressed cell proliferation and induced the death of Ty-82 human thymic carcinoma cells. Fluvastatin mediated its antitumor effects by blocking the production of geranylgeranyl-pyrophosphate (GGPP), an isoprenoid that is produced from mevalonate and binds to small GTPases, which promotes cell proliferation.

Significance: Fluvastatin showed marked antitumor effects on thymic carcinoma. The results suggest that the statin has clinical benefits in thymic carcinoma management.

Keywords: ERK; Fluvastatin; HMG-CoA reductase; Isoprenylation; Thymic carcinoma.

MeSH terms

Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Fluvastatin / therapeutic use*
Humans
Hydroxymethylglutaryl CoA Reductases / biosynthesis
Hydroxymethylglutaryl CoA Reductases / genetics
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Immunohistochemistry
MAP Kinase Signaling System / drug effects
Polyisoprenyl Phosphates / antagonists & inhibitors
Polyisoprenyl Phosphates / biosynthesis
Prenylation / drug effects
Thymoma / drug therapy*
Thymus Neoplasms / drug therapy*

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Polyisoprenyl Phosphates
Fluvastatin
HMGCR protein, human
Hydroxymethylglutaryl CoA Reductases
geranylgeranyl pyrophosphate