title: Induction of hypoxia-inducible factor-1alpha overexpression by cobalt chloride enhances cellular resistance to photodynamic therapy.
abstract: Although photodynamic therapy (PDT) has been approved by regulatory agencies worldwide for the treatment of several oncologic and non-oncologic conditions, PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption limits the efficacy of this modality. This may largely be due to hypoxia-mediated angiogenesis via hypoxia-inducible factor-1alpha (HIF-1alpha), a major transcription factor involved in angiogenesis, hematopoiesis and anaerobic energy metabolism. We hypothesized that hypoxia-induced HIF-1alpha overexpression may also lead to tumor cells resistant to PDT by favouring tumor cell proliferation. Human esophageal normal Het-1A and tumor KYSE-70 and KYSE-450 cell lines were used in the present study. High-expression of HIF-1alpha induced in vitro by cobalt chloride (CoCl(2))-mediated chemical hypoxia mimic was clearly seen in the Het-1A cell line. In addition, cells treated with CoCl(2) were more resistant to 5-aminolevulinic acid (ALA)-mediated PDT than those without CoCl(2) treatment. The photosensitivity of the cells to ALA-PDT decreased with increasing HIF-1alpha expression by enhancing CoCl(2) concentrations. Moreover, transfection of the cells with anti-HIF-1alpha short interfering RNA (siRNA) knocked down the HIF-1alpha expression and restored the photosensitivity of the cells to ALA-PDT. However, the induction of HIF-1alpha expression by CoCl(2) was not indicated in both KYSE-70 and KYSE-450 cell lines, and no difference in cell survival was found after ALA-PDT in the presence and absence of CoCl(2). We thus conclude that high-expression of HIF-1alpha induced by CoCl(2) plays an important role in the resistance of the Het-1A cells to ALA-PDT. The present finding suggests that hypoxia-induced HIF-1alpha overexpression attenuates PDT efficacy through probably not only angiogenesis, but also cellular resistance to the modality. PDT in combination with anti-HIF-1alpha treatment may thus enhance the PDT efficacy.
authors.affiliation: Department of Pathology, The National Hospital-The Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ji
authors.forename: Guanrui
authors.initials: G
authors.lastname: Yang
authors.forename: Susan
authors.initials: S
authors.lastname: Shahzidi
authors.forename: Kinga
authors.initials: K
authors.lastname: Tkacz-Stachowska
authors.forename: Zhenhe
authors.initials: Z
authors.lastname: Suo
authors.forename: Jahn M
authors.initials: JM
authors.lastname: Nesland
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000628:therapy; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D003035:Cobalt / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D004947:Esophagus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008027:Light; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017319:Photosensitizing Agents; D034741:RNA, Small Interfering; D003035:Cobalt; D000622:Aminolevulinic Acid; C018021:cobaltous chloride