A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Abstract

Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation.

Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB

“…Considering the potential association between platinum resistance with the tumor heterogeneity and clinical outcomes of BLCA, we developed the PRR scoring system based on seven key genes associated with platinum resistance. More specifically, ALDH1A1, DSG1, LDLR, NRP2, and P4HB were considered risk factors, while IFNG and IL17A were favorable genes for platinum resistance, which is consistent with the current studies ( 20 – 23 ). As expected, cluster A exhibited the highest PRR score, while cluster C had the lowest PRR score, and cluster B showed a moderate PRR score.…”

Identification and validation of key genes associated with atrial fibrillation in the elderly

“…ALDH1A1 , a member of the ALDH family, is highly expressed by stem cells in cancer ( 55 ). Da et al ( 56 ) recently found that ALDH1A1 was associated with cardiac development and protection after MI.…”

Biology-driven therapy advances in high-grade serous ovarian cancer

“…Key antioxidant molecules, including glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2) ( 166 ), and ALDH1 ( 167 ), are upregulated in cancer stem cells and in resistant cells and tumors ( 151 ). Notably, small molecules that block ALDH activity ( 168 , 169 ) resensitize OC cells to chemotherapy by reducing the antioxidant defense and suppressing Pt-induced senescence and stemness features. Likewise, small-molecule inhibitors targeting GPX4 eliminated Pt-resistant cells via ferroptosis, an iron and lipid peroxidation-dependent form of cell death ( 151 ).…”