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Abstract
Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths globally, with over 40,000 new cases and 30,000 deaths reported in the United States [1,2].Obesity, alcohol consumption, smoking, exposure to aflatoxin, and viral infection are the common risk factors for HCC [1]
In order to improve the anti-proliferative effect of tryptanthrin, twelve tryptanthrin derivatives were synthesized (Figure 1B)
The inhibitory effect of these compounds (A1–A12) on the growth of Hep3B HCC cells was assessed after treatment for 48 h, using an MTT assay
Summary
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths globally, with over 40,000 new cases and 30,000 deaths reported in the United States [1,2].Obesity, alcohol consumption, smoking, exposure to aflatoxin, and viral infection (hepatitisB and C) are the common risk factors for HCC [1]. The current treatment options for HCC include surgery, liver transplant, chemotherapy, radiotherapy, and embolization [3]. There is an urgent need to develop a new therapeutic strategy for the treatment of HCC. Natural products have been used as enriched sources for the prevention and therapy of various diseases, including cancer [5]. Paclitaxel, originally isolated from Taxus brevifolia, alters microtubule polymerization in the cell cycle and is a commonly prescribed anti-cancer drug approved for the treatment of breast cancer, ovarian cancer, lung cancer, and oral cancer by the U.S Food and Drug Administration [7]. Vinorelbine, originally developed from vinca alkaloid, was approved as the first line of treatment for advanced lung cancer in 1994 [8]
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