Cytochrome P450 inhbitors induce anti‐angiogenic cytokine release from H526 SCLC

Abstract

Small Cell Lung Carcinoma (SCLC) is a leading cause of cancer mortality and with the current treatment available, there is only a 20% survival rate at 5 years after diagnosis. Strategies to combat SCLC have focused on novel anti-angiogenic compounds. This project tested the hypothesis that cytochrome P450 (CYP) inhibitors, such as 17-ODYA, work to inhibit the pro-angiogenic factors released by H-526 cells in vitro as a mechanism for in vivo anti-tumorigenic actions. An additional goal of this work was to develop an in vivo model of SCLC in the athymic mouse. H-526 SCLC cells were grown in culture and treated with the following compounds: 17-ODYA, OS #10 and miconazole. Cells were treated for 24 hr with vehicle or CYP inhibitors and the supernatant used to probe an angiogenesis and cytokine antibody array(s) to investigate the effects of these compounds on the angiogenic and cytokine proteins released by H-526 cells. The effects of CYP inhibitors on the release of angiogenic factors was variable however, the effects of the CYP inhibitors on cytokine release were more consistent. Specifically, IL-4, IL-12 and TNFR1 were increased after treatment with all three compounds tested. We also show that the compounds have no direct effect on H-526 proliferation as determined by [3H]-thymidine incorporation. Lastly, preliminary studies indicate that subcutaneous implantation of H-526 cells results in tumor formation within 12 days and will be a useful model for investigating the effect of CYP inhibitors on SCLS in vivo. Our preliminary studies indicate a direct effect of CYP inhibitors on cytokine release in H-526 cells. Future work will focus on signaling mechanisms involved in this effect and also to investigate the effect of CYP inhibitors on tumor formation, angiogenesis and cytokine release in vivo