Isochromanoindolenines suppress triple-negative breast cancer cell proliferation partially via inhibiting Akt activation

Abstract

As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date. In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening. Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065. FZU-0025-065 inhibits TNBC cell growth in a time-and dosage-dependent manner. FZU-0025-065 suppresses the expression of cell cycle dependent kinase 4 (CDK4), Cyclin D1 and Cyclin B1; meanwhile, elevates the expression of cell cycle dependent kinase inhibitor p21 and p27. Importantly, we found that FZU-0025-065 suppresses AKT activation in a time-and dosage-dependent manner. Over-expression of constitutive active AKT partially rescues FZU-0025-065 induced cell growth inhibition in MDA-MB-468 cells, indicating FZU-0025-065 suppresses TNBC cell growth partially via inhibiting AKT activation. Finally, FZU-0025-065 suppresses TNBC cell growth in a xenograft mouse model. Taken together, our findings suggested that isochromanoindolenine derivative FZU-0025-065 inhibits TNBC via suppressing the AKT signaling and that FZU-0025-065 may be useful for TNBC treatment.

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation

“…The lentiviral pCDH-AKT plasmid was kindly provided by Dr. Ceshi Chen from Kunming Medical University (Kunming, China), and virus packaging was performed according to their published protocols 31 . Lentiviruses infected Hep3B and Huh7 cells were selected by 1 μg/ml puromycin for further experiments.…”

Test

“…FZU-0025-065, an isochroman indolenine derivative, partially inhibited AKT activation; suppressed CDK 4, cyclin D1, and cyclin B1; and upregulated CDK inhibitors-p21 and p27. It inhibits DNA synthesis and arrests the cell cycle in G1/G0 phase and has also been reported to inhibit colony formation in a dose-dependent manner [41]. Flavopereirine, an alkaloid natural extract that can also be synthesized chemically, induces cell cycle arrest and apoptosis through the AKT/p38 MAPK/ERK1/2 pathway; of TNBC cells.…”

Data_Sheet_1.DOCX

“…It has been widely reported that the PI3K/AKT signaling pathway plays a role in ovarian follicle development (Li et al, 2017). AKT's activities in increasing proliferation are mediated by the cell cycle regulators Cyclin D1 and Cyclin B1 (Liu et al, 2020;Jiang et al, 2021). As downstream factors of the PI3K/AKT signaling pathway, the antiapoptotic gene Bcl2 and the proapoptotic gene Bax play crucial roles in the regulation of GCs apoptosis during follicular development (Hu et al, 2004;John et al, 2009;Gong et al, 2020).…”