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Apoptosis

, Volume 21, Issue 11, pp 1265–1278 | Cite as

Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer

  • Eun Hye Kim
  • Hyejin Jang
  • Daiha Shin
  • Seung Ho Baek
  • Jong-Lyel RohEmail author
Article

Abstract

A principal limitation to the clinical use of cisplatin is the high incidence of chemoresistance to this drug. Combination treatments with other drugs may help to circumvent this problem. Wogonin, one of the major natural flavonoids, is known to reverse multidrug resistance in several types of cancers. We investigated the ability of wogonin to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Two cisplatin-resistant HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effects of wogonin, either alone or in combination with cisplatin, were assessed in HNC cells and normal cells using cell cycle and death assays and by measuring cell viability, reactive oxygen species (ROS) production, and protein expression, and in tumor xenograft mouse models. Wogonin selectively killed HNC cells but spared normal cells. It inhibited nuclear factor erythroid 2-related factor 2 and glutathione S-transferase P in cisplatin-resistant HNC cells, resulting in increased ROS accumulation in HNC cells, an effect that could be blocked by the antioxidant N-acetyl-l-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and activating cell death pathways involving PUMA and PARP. Hence, wogonin significantly sensitized resistant HNC cells to cisplatin both in vitro and in vivo. Wogonin is a promising anticancer candidate that induces ROS accumulation and selective cytotoxicity in HNC cells and can help to overcome cisplatin-resistance in this cancer.

Keywords

Head and neck cancer Cisplatin resistance Wogonin Reactive oxygen species Cell death 

Abbreviations

HNC

Head and neck cancer

Nrf2

Nf-E2-related factor 2

ARE

Antioxidant response element

ROS

Reactive oxygen species

NAC

N-acetyl-l-cysteine

GSH

Glutathione

GSSG

Glutathione disulfide

DCF-DA

2′,7′-Dichlorofluorescein diacetate

PARP

Poly(ADP-ribose) polymerase

JNK

c-Jun N-terminal kinase

GSTP1

Glutathione S-transferase pi 1

siRNA

Short interfering RNA

TUNEL

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Notes

Acknowledgments

This study was supported by a Grant (No. 2015R1A2A1A15054540) from Basic Science Research Program through the National Research Foundation of Korea (NRF), Ministry of Science, ICT, and Future Planning, and a Grant (No. HI15C2920) from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Ministry of Health & Welfare, Seoul, Republic of Korea (J.-L. Roh).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10495_2016_1284_MOESM1_ESM.tif (3.2 mb)
Supplementary Material 1 (TIFF 3290 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Eun Hye Kim
    • 1
  • Hyejin Jang
    • 1
  • Daiha Shin
    • 1
  • Seung Ho Baek
    • 1
  • Jong-Lyel Roh
    • 1
    Email author
  1. 1.Department of Otolaryngology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea

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