Combinations of metabolic blockers (including fenofibrate) with chemotherapeutic drugs interfere with the drug‐resistance of prostate cancer cells. However, their effect on cancer stem cells‐dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel‐resistant CD133^high and/or CD44^high cancer stem cell‐like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel‐resistant CD44^negative “bulk” cells, thus accounting for the microevolution of drug‐resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug‐resistant CD44^high SCL cells. However, the CD44^negative offspring of docetaxel‐ and docetaxel/fenofibrate‐treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long‐term propagation of drug‐resistant SCL‐derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug‐sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug‐resistant prostate tumors. However, docetaxel/fenofibrate‐induced selective expansion of hyper‐resistant CD44^high SCL prostate cells and their “bulk” progenies prompts the microevolution of prostate tumor drug‐resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.

中文翻译：

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CD44 +细胞决定非诺贝特诱导的前列腺癌细胞群耐药性的微进化

代谢阻断剂（包括非诺贝特）与化学治疗药物的组合会干扰前列腺癌细胞的耐药性。然而，它们对前列腺癌恶性肿瘤干细胞依赖性微进化的影响仍未解决。在这里，我们假设多西他赛/非诺贝特的联合治疗可促进癌症干细胞的选择性扩增，从而影响其子代的微进化。因此，我们采用了组合的体外/体内方法来确定该过程的生物学和治疗效果。多西他赛耐药的CD133^高和/或CD44^高的微小亚群在前列腺癌DU145和PC3细胞群体中发现了癌干细胞样（SCL）细胞。当用多西他赛预处理时，它们很容易分化为多西他赛耐药的CD44^阴性“散装”细胞，从而解释了耐药细胞谱系的微进化。多西他赛/非诺贝特联合治疗诱导多形核巨细胞和耐药CD44^高SCL细胞的生成。但是，CD44^阴性多西紫杉醇和多西紫杉醇/非诺贝特治疗的SCL的后代对联合治疗仍然相对敏感，同时保留了对多西紫杉醇的增强耐药性。在缺乏多西他赛/非诺贝特的情况下，耐药性SCL衍生谱系的长期繁殖导致其向药物敏感性和侵袭性表型的反向微进化。因此，在最初阻止其在体内的扩张后，前列腺肿瘤能够从多西他赛/非诺贝特的联合应激中恢复。总之，我们已经确认了非诺贝特在抗药性前列腺肿瘤的基因组治疗中的潜力。然而，多西他赛/非诺贝特诱导耐超CD44的选择性扩增^高SCL前列腺细胞及其“大量”后代促进了前列腺肿瘤耐药性的微进化。该过程可限制代谢化学疗法在前列腺癌治疗中的实施。