Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin.
Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin.
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DOI：
10.1158/1541-7786.mcr-17-0338
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Mittelman SD
中科院分区：
文献类型：
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作者：
Sheng X;Parmentier JH;Tucci J;Pei H;Cortez-Toledo O;Dieli-Conwright CM;Oberley MJ;Neely M;Orgel E;Louie SG;Mittelman SD
肥胖与许多癌症的预后较差有关。先前，我们观察到脂肪细胞保护急性淋巴细胞白血病（ALL）细胞免受蒽环类药物柔红霉素（DNR）的影响。在本研究中，确定脂肪细胞是否从肿瘤微环境（TME）中清除DNR。荧光法测定细胞内DNR浓度。采用液相色谱/质谱（LC/MS）分析测定培养基、细胞和组织中的DNR及其大部分无活性代谢物-柔比醇。利用公共数据库查询人脂肪组织中醛酮还原酶（AKR1A1、AKR1B1、AKR1C1、AKR1C2、AKR1C3、AKR7A2）和羰基还原酶（CBR1、CBR3）的表达情况，并采用定量PCR （qPCR）和免疫印迹法直接检测。用比色法测定脂肪组织AKR活性。脂肪细胞吸收并有效代谢DNR为柔红霉素，降低其在局部微环境中的抗白血病作用。小鼠研究证实了DNR在体内脂肪组织转化为柔红霉素。脂肪细胞表达高水平的AKR和CBR同工酶，使蒽环类药物失活。事实上，脂肪细胞中AKR1C1、AKR1C2和AKR1C3的蛋白水平高于所有其他人类非癌细胞类型。据我们所知，这是第一次证明脂肪细胞代谢和灭活治疗药物。脂肪细胞介导的DNR代谢降低TME中的活性药物浓度。这些结果对于富含脂肪细胞的癌症微环境如网膜、乳腺和骨髓具有重要的临床意义。由于AKR和CBR酶代谢多种药物，并且在肥胖个体中表达水平较高，因此这一原理证明发现对许多疾病具有重要意义。
Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin (DNR). In the present study, it is determined whether adipocytes clear DNR from the tumor microenvironment (TME). Intracellular DNR concentrations were evaluated using fluorescence. DNR and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of DNR-metabolizing enzymes: aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3) in human adipose tissue were queried using public databases, and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized DNR to daunorubicinol reducing its anti-leukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of DNR to daunorubicinol in vivo. Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human non-cancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated DNR metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. Since AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases.