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.
Highlights
Liver cancer was the second most fatal cancer of all cancer types in 2018 [1]
To determine whether Hemistepsin A (HsA) has an anti-tumor effect, we investigated whether it affected cell viability in various human hepatocellular carcinoma (HCC) cell lines by using the MTT assay
To determine the cellular mechanism that has prevented the proliferation of HCC cell lines, we examined the cell cycle profiles in Huh7 cells treated with HsA at various concentrations or times by using flow cytometry
Summary
About 90% of malignant tumors in the liver are hepatocellular carcinoma (HCC), which mostly occurs in the presence of cirrhosis [2,3]. Surgical methods, such as resection or transplantation, may be applied, if HCC is detected early, beyond the initial stage, chemotherapy is primarily used to stop tumor growth and reduce its size [4,5]. It is necessary to discover new potent compounds that can minimize side effects, and in this sense, it is worth considering natural products. As a result of these needs and efforts, over 60% of current anti-tumor drugs have been derived from natural sources [6,7]
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