Inhibition of hif-1α by atorvastatin during131i-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)-1α 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 of131I-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of131I-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-1α/VEGF (Vascular endothelial growth factor) during ATV combination therapy with131I-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1α in Raji cells. Conclusion: Our findings suggested that combination therapy with ATV and131I-RTX is a promising strategy for enhancing the potency of131I-RTX therapy in poorly responding patients and those with radio-resistance.