Hypoxia-inducible factor 1alpha- mediated resistance to phenolic anticancer.
BACKGROUND
Phenolic compounds EGCG [(-)-epigallocatechin-3-gallate], resveratrol (3,4',5-trihydroxy-trans-stilbene) and capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) are worth investigating for clinical application in cancer prevention and chemotherapy. Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer chemotherapy. Therefore, we examined whether drug resistance to these phenolic compounds is acquired by hypoxia.


METHODS
Hep3B hepatoma, Caki-1 renal carcinoma, SK-N-MC neuroblastoma, and HEK293 cell lines were cultured under normoxic or hypoxic conditions. Drug sensitivities to the phenolic compounds and expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the multidrug resistance genes were examined in these cell lines.


RESULTS
Drug resistance was acquired 24 h after hypoxia and subsided 8 h after reoxygenation. Protein synthesis inhibitors abolished this drug resistance. A transfection study demonstrated that HIF-1alpha enhanced this hypoxia-induced resistance and that its dominant-negative isoform suppressed resistance acquisition. However, MDR1 and MRP1, which provide multidrug resistance to conventional anticancer agents, were not induced by hypoxia.


CONCLUSIONS
These results suggest that HIF-1alpha-dependent gene expression participates in the cellular process of the hypoxia-induced resistance to phenolic compounds.
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
Ju-Yeon
JY
Hyun
Yang-Sook
YS
Chun
Tae-You
TY
Kim
Hye-Lim
HL
Kim
Myung-Suk
MS
Kim
Jong-Wan
JW
Park
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002211:Capsaicin / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
D000970:Antineoplastic Agents; D000975:Antioxidants; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins; D013267:Stilbenes; D014157:Transcription Factors; D002392:Catechin; C045651:epigallocatechin gallate; D000077185:Resveratrol; D002211:Capsaicin