The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions

• Published in: Biochemical and biophysical research communications 2010-07, Vol.398 (1), p.74-78
• Main Authors: Mylonis, Ilias, Lakka, Achillia, Tsakalof, Andreas, Simos, George
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANOXIA; Antineoplastic Agents - pharmacology; Carcinoma, Hepatocellular - metabolism; Cell Hypoxia; Cell Line, Tumor; Cell Survival - drug effects; CHEMOTHERAPY; CONCENTRATION RATIO; CYTOPLASM; Diet; DMSO; FLAVONOIDS; Flavonoids - pharmacology; Hepatocellular carcinoma; HEPATOMAS; HIF-1α; Huh7; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - antagonists & inhibitors; INHIBITION; Kaempferol; Kaempferols - pharmacology; Liver Neoplasms - metabolism; Male; MAPK; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; MORTALITY; OXYGEN; PROTEINS; TOXICITY; TUMOR CELLS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.06.038

► Kaempferol inhibits HIF-1 activity in hepatocarcinoma cells; ► Kaempferol causes cytoplasmic mislocalization of HIF-1α by impairing the MAPK pathway. ► Viability of hepatocarcinoma cells under hypoxia is reduced by kaempferol. Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1α subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1α as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC50=5.16μM). The mechanism of this inhibition did not involve suppression of HIF-1α protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC50=4.75μM). Exposure of Huh7 cells to 10μΜ kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5–10μM) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.