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BioMed Research International
Volume 2013 (2013), Article ID 210604, 14 pages
http://dx.doi.org/10.1155/2013/210604
Research Article

Involvement of Nrf2-Mediated Upregulation of Heme Oxygenase-1 in Mollugin-Induced Growth Inhibition and Apoptosis in Human Oral Cancer Cells

1Department of Maxillofacial Tissue Regeneration and Research Center for Tooth & Periodontal Regeneration, School of Dentistry, Kyung Hee University, 1 Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
2Department of Oral Medicine, School of Dentistry, Kyung Hee University, Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
3Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
4College of Pharmacy, College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea

Received 12 February 2013; Revised 3 April 2013; Accepted 5 April 2013

Academic Editor: George Perry

Copyright © 2013 Young-Man Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Although previous studies have shown that mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin-induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G1 phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF-κB and NF-κB-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM-1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2–related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF-κB.