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Drug Metabolism and Disposition Fast Forward
First published on November 9, 2005; DOI: 10.1124/dmd.105.005280

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Received for publication May 12, 2005.
Revised November 5, 2005.
Accepted for publication November 8, 2005.

Inhibition of Lung Cancer Cell Growth by Quercetin Glucuronides via G2/M Arrest and Induction of Apoptosis

Jen-Hung Yang 1, Te-Chun Hsia 2, Hsiu-Maan Kuo 3, Pei-Daen Lee Chao 4, Chi-Chung Chou 5, Yau-Huei Wei 6, Jing-Gung Chung 7*

1 Chung Shan Medical University Hospital 2 Department of Internal Medicine, China Medical University Hospital 3 Department of Parasitology, China Medical University 4 Department of Pharmacy, China Medical University 5 Department of Veterinary Medicine, National Chung-Hsin University 6 Department of Biochemistry, National Yang-Ming University 7 School of Biological Science and Technology, China Medical University

* Address correspondence to: E-mail: jgchung{at}mail.cmu.edu.tw

Abstract

Lung cancer is the leading cause of cancer death in many developed countries including Taiwan. Quercetin, a widely distributed bioflavonoid, is well known to induce growth inhibition in a variety of human cancer cells. Quercetin glucuronides are the main circulating metabolites after dietary supplement with quercetin in humans. However, there is little information available as to how quercetin glucuronides affect human cancer cells. We investigated the effects of quercetin glucuronides in a human lung cancer cell line NCI-H209. We checked the cell viability, cell cycle checkpoint proteins, pro- and anti-apoptotic proteins, caspases-3 activity; and gene expression by flow cytometry and Western blot. The viability of cells decreased in a dose- and time-dependent manner. Cell cycle analysis revealed a significant increase of proportion of cells in G2/M phase and sub-G0/G1 phase (corresponding to apoptotic cells). Moreover, quercetin glucuronides increased the expressions of cylin B, Cdc25c-ser-216-p and Wee1 proteins, indicating the G2/M arrest. We also demonstrated a concurrent decrease of the mitochondrial membrane potential, release of cytochrome c, up-regulation of Bax, down-regulation of Bcl-2, and activation of caspase-3, subsequently cleavage of poly-(ADP-ribose) polymerase (PARP). In addition, quercetin glucuronides-induced apoptosis was totally blocked by the broad-spectrum caspase inhibitor, z-VAD-fmk. Taken together, we demonstrated that quercetin glucuronides inhibited proliferation through G2/M arrest of the cell cycle and induced apoptosis via caspase-3 cascade in the human lung cancer cell line NCI-H209. Delineation of the biological effects of specific major quercetin metabolites on chemotherapeutic potential or chemoprevention of human cancers warrants further investigation.


Key words: apoptosis, cell death, lung cancer, molecular drug targeting, programmed cell death


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