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Open AccessArticle

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

Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei 10449, Taiwan
Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City 32001, Taiwan
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;
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)
PDF [5260 KB, uploaded 24 August 2018]


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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