Hypoxia-inducible factor-1/spl alpha/ (HIF-1/spl alpha/) and photodynamic therapy

Abstract

Summary form only given. Photodynamic therapy (PDT) is a promising treatment modality that is being tested in the clinic for use in oncology. PDT requires three elements: light, a photosensitizer and oxygen. PDT-mediated oxidative stress elicits direct tumor cell damage and microvascular injury within exposed tumor. Microvasculature damage following PDT leads to a significant decrease in blood flow as well as severe and persistent tumor tissue hypoxia. Subsequently, tissue hypoxia can induce a plethora of molecular and physiological responses, including an adaptive response associated with gene activation. A primary step in hypoxia-mediated gene activation is the formation of the hypoxia-inducible factor (HIF-1) transcription factor complex. Hypoxia induces the stabilization of the HIF-1/spl alpha/, which in turn allows for the formation of the transcriptionally active protein complex. Up to date, the HIF-1-responsive genes that can modulate the PDT response have not been well identified. In the current study, we employed 5-aminolevulinic acid as a photosensitizer, 630 nm wavelength light-emitting diode (LED) manufactured by the Industrial Technology Research Institute as a light source. The experimental results demonstrated that cancer cells are more resistant to PDT under hypoxic status. PDT can transcriptionally induce or enhance HIF-1/spl alpha/ expression in different cervical cancer cell lines (SiHa, HeLa, Caski, C33A, HT-3), immortalized cervical epithelium cell line 183 A, and human umbilical vein endothelial cells (HUVECs). Pharmacological and genetic inhibition assays revealed that PI3K/Akt signaling critically involves in the activation of HIF-1/spl alpha/ by PDT in SiHa cells. When SiHa cells was treated with antisense HIF-1/spl alpha/ (20/spl mu/M), PDT activated HIF-1/spl alpha/ protein expression was markedly inhibited, and subsequently sensitized SiHa cells to PDT. Currently, pharmaceutical companies actively develop novel compounds targeting HIF-1/spl alpha/ as a promising cancer therapy. The results of this study will, therefore, provide important information to improve the therapeutic efficacy of PDT and have great clinical applicable potential.