Nwani Nkechiyere G, Condello Salvatore, Wang Yinu, Swetzig Wendy M, Barber Emma, Hurley Thomas, Matei Daniela
Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.
Department of Obstetrics and Gynecology, Indiana University, Indianapolis, IN 46202, USA.
Cancers (Basel). 2019 Apr 8;11(4):502. doi: 10.3390/cancers11040502.
A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, we describe the activity of CM37, a newly identified small molecule with inhibitory activity against ALDH1A1, in OC models enriched in CSCs. Treatment with CM37 reduced OC cells' proliferation as spheroids under low attachment growth conditions and the expression of stemness-associated markers ( and ) in ALDH+ cells fluorescence-activated cell sorting (FACS)-sorted from cell lines and malignant OC ascites. Likewise, siRNA-mediated knockdown reduced OC cells' proliferation as spheres, expression of stemness markers, and delayed tumor initiation capacity in vivo. Treatment with CM37 promoted DNA damage in OC cells, as evidenced by induction of γH2AX. This corresponded to increased expression of genes involved in DNA damage response, such as , as measured in ALDH+ cells treated with CM37 or in cells where was knocked down. By inhibiting ALDH1A1, CM37 augmented intracellular ROS accumulation, which in turn led to increased DNA damage and reduced OC cell viability. Cumulatively, our findings demonstrate that a novel ALDH1A1 small molecule inhibitor is active in OC models enriched in CSCs. Further optimization of this new class of small molecules could provide a novel strategy for targeting treatment-resistant OC.
一小部分称为癌症干细胞（CSC）的增殖缓慢且对化疗耐药的细胞与癌症复发有关。开发靶向疗法以根除癌症干细胞的兴趣日益浓厚。醛脱氢酶（ALDH）活性被证明是卵巢癌（OC）中癌症干细胞的功能标志物。在分化条件下，与单层培养相比，以球体形式生长的细胞以及铂处理后的OC细胞中，ALDH活性增加。在此，我们描述了CM37（一种新鉴定的对ALDH1A1具有抑制活性的小分子）在富含癌症干细胞的OC模型中的活性。用CM37处理可降低OC细胞在低附着生长条件下作为球体的增殖以及从细胞系和恶性OC腹水中通过荧光激活细胞分选（FACS）分选的ALDH +细胞中干性相关标志物（和）的表达。同样，siRNA介导的敲低降低了OC细胞作为球体的增殖、干性标志物的表达，并延迟了体内肿瘤起始能力。用CM37处理可促进OC细胞中的DNA损伤，γH2AX的诱导证明了这一点。这对应于DNA损伤反应相关基因表达的增加，如在用CM37处理的ALDH +细胞或被敲低的细胞中所测量的那样。通过抑制ALDH1A1，CM37增加了细胞内ROS的积累，这反过来又导致DNA损伤增加和OC细胞活力降低。累积而言，我们的研究结果表明，一种新型的ALDH1A1小分子抑制剂在富含癌症干细胞的OC模型中具有活性。对这类新小分子的进一步优化可为靶向治疗耐药性OC提供一种新策略。
