Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to
chemotherapy failure and drug resistance. As an approach to target
hypoxia, we assessed the potential of
quercetin, a
flavonoid widely distributed in plants, as a
anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of
AMP-activated protein kinase (AMPK).
Quercetin significantly attenuated
tumor growth in an HCT116
cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system,
quercetin more dramatically induced apoptosis of HCT116
cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of
hypoxia-induced AMPK activity. An in vitro
kinase assay demonstrated that
quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under
hypoxia, and a constitutively active form of AMPK effectively blocked
quercetin-induced apoptosis under
hypoxia. Collectively, our data suggest that
quercetin directly inhibits
hypoxia-induced AMPK, which plays a protective role against
hypoxia.
Quercetin also reduced the activity of
hypoxia-inducible factor-1 (HIF-1), a major
transcription factor for adaptive cellular response to
hypoxia. Moreover,
quercetin sensitized HCT116
cancer cells to the anticancer drugs
cisplatin and
etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.