Aspiletrein A Induces Apoptosis Cell Death via Increasing Reactive Oxygen Species Generation and AMPK Activation in Non-Small-Cell Lung Cancer Cells

Abstract

Lung cancer remains a leading cause of death in cancer patients, and deregulation of apoptosis is a serious concern in clinical practice, even though therapeutic intervention has been greatly improved. Plants are a versatile source of biologically active compounds for anticancer drug discovery, and aspiletrein A (AA) is a steroidal saponin isolated from Aspidistra letreae that has a potent cytotoxic effect on various cancer cell lines. In this study, we investigated and determined the underlying molecular mechanism by which AA induces apoptosis. AA strongly induced apoptosis in NSCLC cells by mediating ROS generation and thereby activating AMP-activated protein kinase (AMPK) signaling. Consequently, downstream signaling and levels of phosphorylated mTOR and Bcl-2 were significantly decreased. Pretreatment with either an antioxidant, N-acetylcysteine, or an AMPK inhibitor, compound C, could reverse the apoptosis-inducing effect and counteract the effect of AA on the AMPK signaling pathway. Decreased levels of Bcl-2 were due to AA-mediating Bcl-2 degradation via a ROS/AMPK/mTOR axis-dependent proteasomal mechanism. Consistently, the apoptotic-inducing effect of AA was also observed in patient-derived malignant lung cancer cells, and it suppressed an in vitro 3D-tumorigenesis. This study identified the underlying mechanism of AA on lung cancer apoptosis, thereby facilitating potential research and development of this compound for further clinical implications.

Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

“…Treatment with aspiletrein A led to a decrease in Bcl-2 levels and an increase in caspase 3 and PARP cleavage. The molecular mechanism was identified to be associated with elevated intracellular ROS and activation of AMPK signaling (Witayateeraporn et al, 2022). Network pharmacology analysis also revealed that STAT3 is a target of these compounds in regulating apoptosis (Iksen et al, 2023).…”

“…Aspiletrein A, a steroidal saponin found in Aspidistra letreae , has significant anticancer effects, particularly in lung cancer (Ho et al, 2020; Iksen et al, 2023; Nguyen et al, 2021). In vitro experiments revealed that aspiletrein A induced apoptosis in a dose‐dependent manner (Witayateeraporn et al, 2022). Treatment with aspiletrein A led to a decrease in Bcl‐2 levels and an increase in caspase 3 and PARP cleavage.…”

Serratia marcescens induces apoptosis in Diaphorina citri gut cells via reactive oxygen species‐mediated oxidative stress

“…The potential virulence of Serratia marcescens to Diaphorina citri has been known for years, while the underlying molecular mechanism remains unclear. Reactive oxygen species (ROS) mainly include the superoxide anion (O 2 − ), the hydroxyl radical (OH˙), and hydrogen peroxide (H 2 O 2 ) and play a central role in insect innate immunity by mediating immune signaling or regulating gut microbiota 27,28 . Oral ingestion of Serratia marcescens resulted in an elevation of ROS levels in the midguts of Lutzomyia longipalpis 27 .…”

“…Reactive oxygen species (ROS) mainly include the superoxide anion (O 2 − ), the hydroxyl radical (OH˙), and hydrogen peroxide (H 2 O 2 ) and play a central role in insect innate immunity by mediating immune signaling or regulating gut microbiota. 27,28 Oral ingestion of Serratia marcescens resulted in an elevation of ROS levels in the midguts of Lutzomyia longipalpis. 27 Cell apoptosis or autophagy will be induced under elevated oxidative stress.…”