Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
J Cell Mol Med. 2019 Jun;23(6):4111-4117. doi: 10.1111/jcmm.14298. Epub 2019 Mar 28.
The bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukaemia (AML) and multiple myeloma (MM). We have shown that the critical drug metabolizing enzymes cytochrome P450 (CYP) 3A4 and cytidine deaminase (CDA) are highly expressed by BM stroma, and play an important role in this resistance to chemotherapy. However, what factors influence the chemoprotective capacity of the BM microenvironment, specifically related to CYP3A4 and CDA expression, are unknown. In this study, we found that the presence of AML cells decreases BM stromal expression of CYP3A4 and CDA, and this effect appears to be at least partially the result of cytokines secreted by AML cells. We also observed that stromal CYP3A4 expression is up-regulated by drugs commonly used in AML induction therapy, cytarabine, etoposide and daunorubicin, resulting in cross-resistance. Cytarabine also up-regulated CDA expression. The up-regulation of CYP3A4 associated with disease control was reversed by clarithromycin, a potent inhibitor of CYP3A4. Our data suggest that minimal residual disease states are characterized by high levels of stromal drug metabolizing enzymes and thus, strong microenvironment-mediated drug resistance. These results further suggest a potential role for clinically targeting drug metabolizing enzymes in the microenvironment.
骨髓（BM）微环境有助于急性髓系白血病（AML）和多发性骨髓瘤（MM）的耐药性。我们已经表明，关键的药物代谢酶细胞色素 P450（CYP）3A4 和胞苷脱氨酶（CDA）由 BM 基质高度表达，并在这种化疗耐药中发挥重要作用。然而，影响 BM 微环境的化学保护能力的因素尚不清楚，特别是与 CYP3A4 和 CDA 表达相关的因素。在这项研究中，我们发现 AML 细胞的存在降低了 BM 基质中 CYP3A4 和 CDA 的表达，这种影响至少部分是 AML 细胞分泌的细胞因子的结果。我们还观察到，通常用于 AML 诱导治疗的药物阿糖胞苷、依托泊苷和柔红霉素上调了基质 CYP3A4 的表达，导致交叉耐药。阿糖胞苷也上调了 CDA 的表达。CYP3A4 的上调与疾病控制相关，被强力抑制 CYP3A4 的克拉霉素逆转。我们的数据表明，微小残留病状态的特点是基质药物代谢酶水平高，因此，微环境介导的耐药性很强。这些结果进一步表明，临床上靶向药物代谢酶在微环境中的作用具有潜在的可能性。
