Dihydroaustrasulfone Alcohol Induces Biphasic Autophagy and Apoptosis in Leukemia Cells via PI3K/Akt and JNK Signaling Pathways
TL;DR
DA elicits a biphasic cellular response in U937 leukemia cells, characterized by transient cytoprotective autophagy followed by apoptotic cell death mediated through dysregulation of Bcl-2/Bax and suppression of the PI3K/Akt pathway, indicating that DA is a promising candidate for novel antileukemic therapeutic strategies.
Abstract
Background/Aim: Dihydroaustrasulfone alcohol (DA), a synthetic precursor of austrasulfone derived from the soft coral Cladiella australis, has demonstrated cytotoxic activity against various cancer types. However, its antitumor effects and underlying mechanisms in human leukemia cells remain unknown. This study aimed to investigate the anticancer effects of DA in leukemia cell models and to elucidate its mechanisms of action. Materials and Methods: Human leukemia cell lines U937 and HL-60 were treated with DA (0–50 μM) for 24 and 48 h. Cell viability was assessed utilizing the Cell Counting Kit-8 (CCK-8) assay. Apoptosis and cell cycle distribution were examined through flow cytometry using Annexin V/PI and PI/RNase staining, respectively. The expression levels of proteins related to apoptosis, autophagy, and signaling pathways were determined via western blot analysis. Results: DA decreased cell viability in a dose- and time-dependent manner. The IC50 values for U937 cells were 15.14 μM and 13.6 μM at 24 and 48 h, respectively; for HL-60 cells, these values were 19.36 μM and 15.93 μM. DA induced SubG1-phase cell cycle arrest (11.6% at 24 h; 39.9% at 48 h) and enhanced apoptosis, as evidenced by increased Bax and PARP-1 cleavage and decreased Bcl-2 expression. At 24 h, DA temporarily induced autophagy, as shown by elevated LC3-II/LC3-I ratios and reduced p62 and Atg5 levels; however, autophagic flux was suppressed at 48 h. Furthermore, DA inhibited phosphorylation of PI3K p85 at 24 h and activated JNK phosphorylation at both time points. Conclusion: DA elicits a biphasic cellular response in U937 leukemia cells, characterized by transient cytoprotective autophagy followed by apoptotic cell death mediated through dysregulation of Bcl-2/Bax and suppression of the PI3K/Akt pathway. These findings indicate that DA is a promising candidate for novel antileukemic therapeutic strategies.