Abstract
Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo. TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo, TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo, which in consistent with the effects in vitro. Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.
Highlights
Breast cancer is one of the most common neoplasms worldwide, which occurs mostly in women aged 15–59 years (He and Chen, 2012; Chen et al, 2018)
The percentages of MCF-7 cells in G2/M phase were 10.65% (Control), 26.90% (TAIII 10 μM), and 42.49% (TAIII 15 μM) respectively (Figure 1A). These results demonstrat that Timosaponin AIII (TAIII) induces cell cycle arrest at G2/M phase in breast cancer cells in a concentration-dependent manner
TAIII is a steroidal saponin compound isolated from the ethanol extract of Anemarrhena asphodeloide, and its remarkable antitumor activities have attracted the attention of many scholars, which are associated with the induction of autophagy, cell cycle arrest, apoptosis and suppression of migration and invasion (Takeda et al, 2001; Sy et al, 2008; King et al, 2009; Kang et al, 2011; Tsai et al, 2013; Wang et al, 2013; Huang et al, 2015; Jung et al, 2016; Kim et al, 2016; Nho et al, 2016; Wang et al, 2017; Gergely et al, 2018; Marelia et al, 2018)
Summary
Breast cancer is one of the most common neoplasms worldwide, which occurs mostly in women aged 15–59 years (He and Chen, 2012; Chen et al, 2018). Many breast cancer patients presented distinct metastasis, including lymph nodes, lung liver, and bone marrow (Muller et al, 2001). Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents (GonzalezAngulo et al, 2007). Despite exciting progress in the understanding of breast cancer development and progression, and in the development of novel therapeutic strategies in recent years, according to statistics, breast cancer is still the most common cancer diagnosed among women and is the second leading cause of cancer death among women after. Timosaponin AIII Induces G2/M Arrest lung cancer in United States by 2020 (Siegel et al, 2020). Breast cancer remains a considerable health burden and development of novel therapy against breast cancer is urgent
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