Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Division of Hematology-Oncology, Department of Internal Medicine, Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Cell Rep. 2019 Mar 12;26(11):3061-3075.e6. doi: 10.1016/j.celrep.2019.02.032.
Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer "stemness," and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133 ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.
卵巢癌的特点是化疗耐药性的发展。化疗耐药性与高醛脱氢酶（ALDH）酶活性、癌症“干性”增加以及干细胞标记物 CD133 的表达有关。因此，ALDH 活性已被提议作为一种治疗靶点。尽管 19 种 ALDH 家族成员中哪一种导致化疗耐药性仍存在争议，但 ALDH1A 家族成员主要与化疗耐药性和干性有关。我们鉴定了两种 ALDH1A 家族选择性抑制剂（ALDH1Ai）。ALDH1Ai 优先杀死 CD133 卵巢癌干细胞样细胞（CSC）。ALDH1Ai 通过诱导线粒体解偶联蛋白和减少氧化磷酸化来诱导 CSC 坏死性死亡。ALDH1Ai 与化疗具有高度协同作用，降低肿瘤起始能力并增加体内肿瘤清除率。这些研究将 ALDH1A 与坏死性凋亡联系起来，并证实该家族是克服化疗耐药性和改善患者预后的关键治疗靶点。
