Journal
ANIMAL CELLS AND SYSTEMS
Volume 25, Issue 2, Pages 119-127Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/19768354.2021.1915380
Keywords
Betulinic acid; leukemia cells; G2; M arrest; apoptosis; ROS
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Funding
- National Research Foundation of Korea [4199991013864] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Betulinic acid (BA) exhibits anti-cancer properties in U937 leukemia cells by inducing cell cycle arrest at G2/M phase and apoptosis through mechanisms such as increasing ROS levels, down-regulating cyclins, increasing p21WAF1/CIP1 expression, reducing mitochondrial membrane potential, activating caspases, and triggering cytochrome c release.
Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.
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