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Open AccessArticle

Heme Oxygenase-1 Inhibitors Induce Cell Cycle Arrest and Suppress Tumor Growth in Thyroid Cancer Cells

1
Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei 10449, Taiwan
2
Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City 32001, Taiwan
3
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(9), 2502; https://doi.org/10.3390/ijms19092502
Received: 15 June 2018 / Revised: 17 August 2018 / Accepted: 22 August 2018 / Published: 24 August 2018
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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Abstract

Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo. View Full-Text
Keywords: heme oxygenase; metabolism; reactive oxygen species; thyroid cancer heme oxygenase; metabolism; reactive oxygen species; thyroid cancer
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Yang, P.-S.; Hsu, Y.-C.; Lee, J.-J.; Chen, M.-J.; Huang, S.-Y.; Cheng, S.-P. Heme Oxygenase-1 Inhibitors Induce Cell Cycle Arrest and Suppress Tumor Growth in Thyroid Cancer Cells. Int. J. Mol. Sci. 2018, 19, 2502.

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