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.

• Authors: Xiaoyan Jiang, Xu Zhi, Peixia Zhang, Zhongmei Zhou, Jinxiang Ye, Yu Gao, Xinye Wang, Chuanyu Yang, Haijun Chen, Rong Liu, Ceshi Chen
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 17 Issue 4 Pg. 986-994 ( 2021) ISSN: 1449-2288 [Electronic] Australia
• PMID: 33867823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Cell Cycle Proteins
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Mice, Nude
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays
• Mice