Hemistepsin A Inhibits Cell Proliferation and Induces G0/G1-Phase Arrest, Cellular Senescence and Apoptosis Via the AMPK and p53/p21 Signals in Human Hepatocellular Carcinoma.

Abstract

Hemistepsin A (HsA), a natural sesquiterpene lactone isolated from Hemistepta lyrata, has been known as a wide range of anti-tumor effects. The aim of this study was to determine whether HsA suppresses hepatocellular carcinoma (HCC) and to figure out the cellular signaling pathways involved in the anti-HCC activities by experiments using the Huh7 cells (a human HCC cell line) and a xenograft HCC model. In this study, HsA completely inhibited HCC cell proliferation, presumably because it induced G0/G1 cell cycle arrest and mitochondrial-related apoptosis. HsA up-regulated p53, p21, cleaved caspase-3 and cleaved PARP (poly (ADP-ribose) polymerase), but reduced cyclin D, CDK6 and Bcl-2 expressions, and it disrupted mitochondrial membrane potential (ΔΨm). Moreover, phosphorylation of AMP-activated protein kinase (AMPK) was increased by HsA as did the resveratrol and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, positive controls). Inhibition of AMPK by using compound C, a competent inhibitor of AMPK, attenuated the loss of ΔΨm, p53 up-regulation and cellular senescence. The efficacy of HsA to reduce HCC cell proliferation, compared to that of other known anti-HCC agents, appears to be similar or slightly better. The anti-tumor effect of HsA was also determined in mice, showing reduced growth of xenografted tumors with no weight loss. Overall, the results suggest that HsA should be considered as a candidate anti-HCC drug.

• Authors: Su Youn Baek, Ui Wook Hwang, Ho Young Suk, Young Woo Kim
• Journal: Biomolecules (Biomolecules) Vol. 10 Issue 5 (05 04 2020) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 32375410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Lactones
• Sesquiterpenes
• Tumor Suppressor Protein p53
• hemistepsin
• Protein Kinases
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Proliferation (drug effects)
• Cellular Senescence
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• G1 Phase Cell Cycle Checkpoints
• Hep G2 Cells
• Humans
• Lactones (pharmacology, therapeutic use)
• Liver Neoplasms (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Kinases (metabolism)
• Sesquiterpenes (pharmacology, therapeutic use)
• Signal Transduction
• Tumor Suppressor Protein p53 (metabolism)