PT  - JOURNAL ARTICLE
AU  - Jen-Hung Yang
AU  - Te-Chun Hsia
AU  - Hsiu-Maan Kuo
AU  - Pei-Dawn Lee Chao
AU  - Chi-Chung Chou
AU  - Yau-Huei Wei
AU  - Jing-Gung Chung
TI  - INHIBITION OF LUNG CANCER CELL GROWTH BY QUERCETIN GLUCURONIDES VIA G<sub>2</sub>/M ARREST AND INDUCTION OF APOPTOSIS
AID  - 10.1124/dmd.105.005280
DP  - 2006 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 296--304
VI  - 34
IP  - 2
4099  - http://dmd.aspetjournals.org/content/34/2/296.short
4100  - http://dmd.aspetjournals.org/content/34/2/296.full
SO  - Drug Metab Dispos2006 Feb 01; 34
AB  - 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 supplements 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 antiapoptotic proteins, caspase-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 the proportion of cells in G2/M phase and subG0/G1 phase (corresponding to apoptotic cells). Moreover, quercetin glucuronides increased the expressions of cyclin 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, and subsequently, cleavage of poly(ADP-ribose) polymerase. In addition, quercetin glucuronide-induced apoptosis was totally blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone. 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. The American Society for Pharmacology and Experimental Therapeutics