ALDH1A1 inhibitor 974 (Compound 974) is a first-in-class, highly potent and specific ALDH1A1 inhibitor with IC50 of 470 nM, suppresses chemotherapy-induced senescence as well as stemness.
Compound 974 (5 µM for 48 h) significantly reduces the percentage of ALDH-positive cells in OVCAR3 and OVCAR5 cells, does not affect the proliferation of normal ovarian cells.
Compound 974 significantly decreases the expression of the well-known stemness genes Bmi-1, Nanog, Oct4, and Sox2 in OVCAR3 and OVCAR5 cells.
Compound 974 significantly reduces cancer stem cells (CSC) frequency in mice, suppresses ovarian cancer stemness in vivo.
Compound 974 suppresses pathways involved in chemoresistance and stemness, significantly downregulates the senescence biomarkers p21(CDKN1A) and p15INK4b (CDKN2B) and genes associated with the senescence-associated secretory phenotype (SASP), including IL6, IL8, CXCL1, and CXCL3.
Compound 974 suppressed CDDP-induced senescence-associated beta galactosidase (SA-β gal) staining in OVCAR3 cells, also significantly reduces the basal and CDDP-induced expression of senescence marker p21 (CDKN1A) in OVCAR3 cells and SASP gene expression in OVCAR3 and OVCAR5 cells.