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Inhibition of HIF-1? by Atorvastatin During 131I-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? 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 131I-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of 131I-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?/VEGF (Vascular endothelial growth factor) during ATV combination therapy with 131I-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1? in Raji cells. CONCLUSION:Our findings suggested that combination therapy with ATV and 131I-RTX is a promising strategy for enhancing the potency of 131I-RTX therapy in poorly responding patients and those with radio-resistance.

SUBMITTER: Kim EH

PROVIDER: S-EPMC7281655 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Inhibition of HIF-1α by Atorvastatin During <sup>131</sup>I-RTX Therapy in Burkitt's Lymphoma Model.

Kim Eun-Ho EH Ko Hae Young HY Yu A Ram AR Kim Hyeongi H Zaheer Javeria J Kang Hyun Ji HJ Lim Young-Cheol YC Cho Kyung Deuk KD Joo Hyun-Yoo HY Kang Min Kyoung MK Lee Jae Jun JJ Lee Seung-Sook SS Kang Hye Jin HJ Lim Sang Moo SM Kim Jin Su JS

Cancers 20200511 5

<h4>Backgrounds</h4>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.<h4>Methods</h4>We investigated whether ATV downregulated tumor radio-resistance and enhanced the anticancer effect of <sup>131</sup>I-RTX (rituximab) in Raji xenograft mouse models. First, the increased ...[more]

PMID: 32403237

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Project description:BackgroundBurkitt's lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children.MethodsWe studied low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) in patients with untreated Burkitt's lymphoma. Two EPOCH-R regimens were tested: a standard dose-adjusted combination in human immunodeficiency virus (HIV)-negative patients (DA-EPOCH-R group) and a lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR group).ResultsA total of 30 consecutive patients were treated; 19 patients were in the DA-EPOCH-R group, and 11 in the SC-EPOCH-RR group. The overall median age of the patients was 33 years, and 40% were 40 years of age or older; 73% of the patients had intermediate-risk disease, and 10% had high-risk disease. The principal toxic events, fever and neutropenia, were observed during 22% of the DA-EPOCH-R treatment cycles and 10% of the SC-EPOCH-RR treatment cycles. The tumor lysis syndrome developed in 1 patient; no treatment-related deaths occurred. The median cumulative doses of doxorubicin-etoposide and cyclophosphamide administered in the SC-EPOCH-RR group were 47% and 57% lower, respectively, than those administered in the DA-EPOCH-R group. With median follow-up times of 86 months in the DA-EPOCH-R group and 73 months in the SC-EPOCH-RR group, the rates of freedom from progression of disease and overall survival were, respectively, 95% and 100% with DA-EPOCH-R and 100% and 90% with SC-EPOCH-RR. None of the patients died from Burkitt's lymphoma.ConclusionsIn this uncontrolled prospective study, low-intensity EPOCH-R-based treatment was highly effective in adults with sporadic or immunodeficiency-associated Burkitt's lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov numbers, NCT00001337 and NCT00006436.).

Dataset Information

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

Publications

Inhibition of HIF-1α by Atorvastatin During <sup>131</sup>I-RTX Therapy in Burkitt's Lymphoma Model.

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