Abstract 2960: Adipocytes sequester and metabolize daunorubicin

Abstract

Abstract Obesity is associated with poorer outcome from many cancers, including childhood acute lymphoblastic leukemia (ALL). We have previously shown that adipocytes protect ALL cells from the anthracycline, daunorubicin (DNR). We therefore investigated whether adipocytes sequester and/or metabolize DNR in the ALL microenvironment. Using fluorescence and LC/MS measures, we demonstrated that adipocytes absorb DNR, reducing the intracellular DNR concentration in co-cultured BV173 ALL cells (after 48 hours, median fluorescent intensity of ALL cultured with adipocytes was 1.7±1.0 vs. 5.0±1.7 of those cultured alone, p<0.01). Mouse adipocytes convert DNR to the less active metabolite, daunorubicinol (DNR-ol); over 48 hours, media DNR decreased to 0.1±0.2 (vs. 24.8±8.76 ng/mL in control wells). At the same time, DNR-ol increased to 15.0±1.9 (vs. 0.7±0.6 in control wells; both p<0.05). Similar conversion of DNR to DNR-ol was observed in both mouse adipose explants and human adipose tissue biopsy samples ex vivo. qPCR confirmed human subcutaneous adipose tissue expresses several enzymes capable of metabolizing DNR, including AKR1A1, 1B1, 1C1, 1C2, 1C3, 7A2, and CBR1 and 3 (expression ranged between 20 and 195% β-actin). Using immunohistochemistry, we confirmed expression of AKR1C1, 1C2, and 1C3 in bone marrow adipocytes of children during the first month of treatment for ALL. Finally, two hours after an intravenous dose of DNR in mice, we found that the DNR-ol to DNR ratio was higher in subcutaneous (0.60±0.26) and omental (0.55±0.21) adipose than in white blood cells (0.16±0.11), bone marrow (undetectable DNR-ol), and spleen (undetectable DNR-ol). Together, these data demonstrate that adipocytes sequester and inactivate DNR, likely due to their expression of AKR and CBR enzymes. These findings uncover a novel and important mechanism which could promote local anthracycline resistance by cancer cells in microenvironment rich in adipocytes, such as bone marrow, omentum, and breast. Citation Format: Xia Sheng, Jean-Hugues Parmentier, Jonathan Tucci, Hua Pei, Omar Cortez-Toledo, Christina Dieli-Conwright, Matthew Oberley, Michael Neely, Etan Orgel, Stan Louie, Steven D. Mittelman. Adipocytes sequester and metabolize daunorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2017-2960