Abstract
The synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) is a potent analog of curcumin that exhibits enhanced biological activity and bioavailability without increasing toxicity. EF24 exerts antitumor activity by arresting the cell cycle and inducing apoptosis, suppressing many types of cancer cells in vitro. The antiproliferative and antiangiogenic properties of EF24 provide theoretical support for its development and application to liver cancers. We investigated the in vitro and in vivo activities of EF24 on liver cancer to better understand its therapeutic effects and mechanisms. EF24 induced significant apoptosis and G2/M-phase cell cycle arrest in mouse liver cancer cell lines, Hepa1-6 and H22. The expression levels of G2/M cell cycle regulating factors, cyclin B1 and Cdc2, were significantly decreased, pp53, p53, and p21 were significantly increased in EF24-treated cells. In addition, EF24 treatment significantly reduced Bcl-2 concomitant with an increase in Bax, enhanced the release of cytochrome c from the mitochondria into the cytosol, resulting in an upregulation of cleaved-caspase-3, which promoted poly (ADP-ribose) polymerase cleavage. EF24-treated cells also displayed decreases in phosphorylated Akt, phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. Our in vitro protein expression data were confirmed in vivo using a subcutaneous hepatocellular carcinoma (HCC) tumor model. This mouse HCC model confirmed that total body weight was unchanged following EF24 treatment, although tumor weight was significantly decreased. Using an orthotopic HCC model, EF24 significantly reduced the liver/body weight ratio and relative tumor areas compared to the control group. In situ detection of apoptotic cells and quantification of Ki-67, a biomarker of cell proliferation, all indicated significant tumor suppression with EF24 treatment. These results suggest that EF24 exhibits anti-tumor activity on liver cancer cells via mitochondria-dependent apoptosis and inducing cell cycle arrest coupled with antiangiogenesis. The demonstrated activities of EF24 support its further evaluation as a treatment for human liver cancers.
Highlights
Hepatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma, the fifth most common cancer, and the third leading cause of cancer-related deaths in the world [1,2,3]
EF24 Inhibits Cell Proliferation and Reduces Cell Viability Using the Cell Counting Kit-8 (CCK-8) assay, we evaluated the effect of EF24 on the proliferation of Hepa1-6 and H22 cells
Liver cancer cells incubated with EF24 (4 mM) for 48 h were assessed by Western blotting using antibodies that recognize the intact (116 kDa) and cleaved (89 kDa) forms of poly (ADP-ribose) polymerase (PARP) as well as other apoptosis-related proteins
Summary
Hepatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma, the fifth most common cancer, and the third leading cause of cancer-related deaths in the world [1,2,3]. HCC poses a sociomedical problem in Asia and sub-Saharan Africa, where the number of deaths nearly equal the number of cases diagnosed annually (about 600,000), and the 5-year survival rate is below 9% [4,5,6,7]. The cure rate for patients who undergo resection is relatively low, and among patients who are ineligible for surgical or percutaneous procedures, only chemoembolization improves survival. HCC is widely regarded as a chemotherapy-resistant disease [8,9,10,11,12]. These drawbacks necessitate the continued search for novel HCC therapies
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