Effect of HIF-1 modulation on the response of two- and three-dimensional cultures of human colon cancer cells to 5-fluorouracil.
Tumour hypoxia represents a major obstacle to the success of radiotherapy and chemotherapy. The discovery that the hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular response to low oxygen led to the concept that inhibiting HIF-1 activity may sensitise hypoxic cancer cells to radiation and cytotoxic drugs. In the present study we investigate the effects of HIF-1 modulation on the response of the human colon adenocarcinoma cell line HCT116 to 5-fluorouracil (5FU). Increasing HIF-1 activity, either by exposing cells to hypoxia or by forced expression of a degradation-resistant form of HIF-1alpha, results in poor cell response to 5FU; conversely, knockdown of HIF-1alpha by RNA interference prevents hypoxia-induced resistance to 5FU. PMX290, a thioredoxin-1 inhibitor, significantly inhibits HIF-1 activity and concomitantly sensitises hypoxic cells to 5FU. These results were confirmed in HCT116 cells grown as three-dimensional spheroids, a model that more closely reproduces the hypoxic environment of solid tumours.
Ravizza
Raffaella
R
Department of Structural and Functional Biology, University of Insubria, Section of Pharmacology, Busto Arsizio, Varese, Italy.
Molteni
Roberta
R
Gariboldi
Marzia B
MB
Marras
Emanuela
E
Perletti
Gianpaolo
G
Monti
Elena
E
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D018874:Spheroids, Cellular; D013450:Sulfones / Q000494:pharmacology; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured
C515225:AJM 290; D000964:Antimetabolites, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D009363:Neoplasm Proteins; D013450:Sulfones; C491203:TXN protein, human; D013879:Thioredoxins; D005472:Fluorouracil