Department of Oncology, CR-UK/YCR Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.
Cell Oncol (Dordr). 2013 Dec;36(6):505-14. doi: 10.1007/s13402-013-0156-2. Epub 2013 Nov 1.
Multiple cell types of the tumour microenvironment, including macrophages, contribute to the response to cancer therapy. The anti-resorptive agent zoledronic acid (ZOL) has anti-tumour effects in vitro and in vivo, but it is not known to what extent macrophages are affected by this agent. We have therefore investigated the effects of ZOL on macrophages using a combination of in vitro and in vivo models.
J774 macrophages were treated with ZOL in vitro, alone and in combination with doxorubicin (DOX), and the levels of apoptosis and necrosis determined. Uptake of zoledronic acid was assessed by detection of unprenylated Rap1a in J774 macrophages in vitro, in peritoneal macrophages and in macrophage populations isolated from subcutaneously implanted breast cancer xenografts following ZOL treatment in vivo.
Exposure of J774 macrophages to 5 μM ZOL for 24 h caused a significant increase in the levels of uRap1A, and higher doses/longer exposure induced apoptotic cell death. DOX (10 nM/24 h) and ZOL (10 μM/4 h) given in sequence induced significantly increased levels of apoptotic cell death compared to single agents. Peritoneal macrophages and macrophage populations isolated from breast tumour xenografts had detectable levels of uRap1A 24 h following a single, clinically achievable dose of 100 μg/kg ZOL in vivo.
We demonstrate that macrophages are sensitive to sequential administration of DOX and ZOL, and that both peritoneal and breast tumour associated macrophages rapidly take up ZOL in vivo. Our data support that macrophages may contribute to the anti-tumour effect of ZOL.
肿瘤微环境中的多种细胞类型，包括巨噬细胞，有助于癌症治疗的反应。抗吸收剂唑来膦酸（zoledronic acid，ZOL）在体外和体内均具有抗肿瘤作用，但尚不清楚该药物对巨噬细胞的影响程度。因此，我们使用体外和体内模型相结合的方法研究了 ZOL 对巨噬细胞的影响。
J774 巨噬细胞在体外单独和联合多柔比星（doxorubicin，DOX）用 ZOL 处理，并确定细胞凋亡和坏死的水平。通过检测体外 J774 巨噬细胞、腹腔巨噬细胞和皮下植入乳腺癌异种移植瘤中分离的巨噬细胞群中未prenylated Rap1a 的摄取来评估唑来膦酸的摄取。
J774 巨噬细胞暴露于 5 μM ZOL 24 小时会导致 uRap1A 水平显著增加，更高剂量/更长暴露时间会诱导细胞凋亡。与单一药物相比，顺序给予 DOX（10 nM/24 h）和 ZOL（10 μM/4 h）会诱导显著增加的细胞凋亡水平。在体内给予单次临床可达到的 100μg/kg ZOL 后 24 小时，腹腔巨噬细胞和从乳腺癌异种移植瘤中分离的巨噬细胞群中可检测到 uRap1A 的水平。
我们证明巨噬细胞对 DOX 和 ZOL 的序贯给药敏感，并且腹腔和乳腺癌相关巨噬细胞在体内迅速摄取 ZOL。我们的数据支持巨噬细胞可能有助于 ZOL 的抗肿瘤作用。
