Induction of hypoxia-inducible factor-1α overexpression by cobalt chloride enhances cellular resistance to photodynamic therapy

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-1α (HIF-1α), a major transcription factor involved in angiogenesis, hematopoiesis and anaerobic energy metabolism. We hypothesized that hypoxia-induced HIF-1α 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-1α induced in vitro by cobalt chloride (CoCl2)-mediated chemical hypoxia mimic was clearly seen in the Het-1A cell line. In addition, cells treated with CoCl2 were more resistant to 5-aminolevulinic acid (ALA)-mediated PDT than those without CoCl2 treatment. The photosensitivity of the cells to ALA–PDT decreased with increasing HIF-1α expression by enhancing CoCl2 concentrations. Moreover, transfection of the cells with anti-HIF-1α short interfering RNA (siRNA) knocked down the HIF-1α expression and restored the photosensitivity of the cells to ALA–PDT. However, the induction of HIF-1α expression by CoCl2 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 CoCl2. We thus conclude that high-expression of HIF-1α induced by CoCl2 plays an important role in the resistance of the Het-1A cells to ALA–PDT. The present finding suggests that hypoxia-induced HIF-1α overexpression attenuates PDT efficacy through probably not only angiogenesis, but also cellular resistance to the modality. PDT in combination with anti-HIF-1α treatment may thus enhance the PDT efficacy.