Department of Urology, Center for Urologic Cancer, Hospital Division of Tumor Immunology, Research Institute National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Department of Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Prostate. 2020 May;80(6):453-462. doi: 10.1002/pros.23946. Epub 2020 Mar 5.
Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them.
We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel.
Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank.
The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together.
This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.
多西紫杉醇是激素难治性前列腺癌（PC）患者的首选化疗药物。然而，患者最终会产生多西紫杉醇耐药性，并且对他们来说没有有效的治疗选择。
我们旨在建立去势抵抗性前列腺癌（CRPC）细胞系（DU145/TXR、PC-3/TXR 和 CWR22/TXR）中的多西紫杉醇耐药性，并对获得多西紫杉醇耐药性后转录变化进行特征描述。
人前列腺癌细胞（DU145、PC-3、CWR22）和所有多西紫杉醇耐药细胞均在添加 10%胎牛血清和 1%青霉素/链霉素的罗格斯大学纪念医院培养基（RPMI）1640 培养基中维持。使用流式细胞术制备的亲本和多西紫杉醇耐药性 CRPC 来检测 ABCB1。为了评估每种化疗药物下的肿瘤抑制作用，将 DU145 或 DU145/TXR 的皮下异种移植物植入小鼠的侧腹。
多西紫杉醇耐药细胞中编码 P-糖蛋白的基因 ABCB1 明显上调，其过表达在 CRPC 中的多西紫杉醇耐药中起着重要作用。当测试另一种化疗选择吉西他滨的细胞毒性时，多西紫杉醇耐药细胞对该药物变得敏感，这表明多西紫杉醇耐药细胞发生了额外的表型转化。使用异种移植动物模型的研究表明，当联合使用多西紫杉醇和吉西他滨时，由多西紫杉醇敏感和多西紫杉醇耐药细胞组成的肿瘤的生长受到最显著的抑制。
本研究表明，当一种药物产生治疗耐药性时，敏感性测试可能是另一种选择，最终为新的临床策略提供了启示。
