Inhibition of HIF-1 alpha by Atorvastatin During I-131-RTX Therapy in Burkitt's Lymphoma Model

Abstract

Backgrounds: Radioimmunotherapy (RIT) serves as a targeted therapy for non-Hodgkin lymphomas (NHL). Although HIF(Hypoxia-inducible factors)-1 alpha is an important biomarker during radiation therapy, its role in NHL is unclear. Atorvastatin (ATV) is used as a combination drug for chemotherapy. Methods: We investigated whether ATV downregulated tumor radio-resistance and enhanced the anticancer effect of I-131-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of I-131-RTX by ATV was confirmed using molecular imaging in Raji xenograft subcutaneous model and orthotropic model with SPECT and IVIS images. Second, we examined the profile of differentially expressed miRNAs using miRNA array. Results: We found that miR-346 inhibited HIF-1 alpha /VEGF (Vascular endothelial growth factor) during ATV combination therapy with I-131-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1 alpha in Raji cells. Conclusion: Our findings suggested that combination therapy with ATV and I-131-RTX is a promising strategy for enhancing the potency of I-131-RTX therapy in poorly responding patients and those with radio-resistance.