Cancer Letters

Cancer Letters

Volume 306, Issue 2, 28 July 2011, Pages 190-196
Cancer Letters

Anti-cancer effects of a novel compound HS-113 on cell growth, apoptosis, and angiogenesis in human hepatocellular carcinoma cells

https://doi.org/10.1016/j.canlet.2011.03.005Get rights and content

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies, yet there have been no significant advances in effective therapeutics. In this study, HS-113 was synthesized as a novel compound, N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2-carboxamide and its cytotoxic activity and anti-cancer effect were examined in human HCC cells. HS-113 strongly suppressed growth of HCC cells in a dose-dependent manner, induced apoptosis by increasing the proportion of sub-G1 apoptotic cells, and caused cell cycle arrest at G0/G1 phase. Also, HS-113 increased the expression of p27 and decreased that of cyclin D1 associated with cell cycle arrest. Apoptosis by HS-113 was confirmed by DAPI and TUNEL staining, and the increases of the cleaved PARP and caspase-3 were observed. Furthermore, HS-113 decreased protein expression of HIF-1α and secretion of VEGF, and inhibited the tube formation of HUVECs. These results showed that HS-113 not only inhibited cell growth and angiogenesis, but also induced apoptosis of human HCC cells. We suggest that HS-113 may be a potential candidate for caner therapy against HCC.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1]. The prognosis of HCC patients is generally very poor. Most studies have shown a 5-year survival rate of less than 5% in patients. To date, surgery is still the only curative treatment but is only feasible in a small portion of patients and the postoperative recurrence rate is also high [2], [3]. Chemotherapy is common treatment applied for inoperable HCC. However, its results are often discouraging because of resistance against anti-cancer drugs and toxicity to normal cells. Thus, a novel pharmaceutical therapy needs to be developed for patients with advanced HCC.

Several benzofuran derivatives have been paid attention due to their biological activities and their potential applications as pharmacological agents. Recently, some of 3-substiuted-5-(benzofuran-2-yl)-pyrazole derivatives exhibited significant anti-microbial activities against various microorganisms [4]. Among the benzofuran derivatives, thiadiazoles also showed a broad spectrum of biological effectiveness such as hypoglycaemic, anti-inflammatory, anti-cancer activities. In addition, thiazole amine derivatives have been reported to possess anti-bacterial, anti-fungal, and anti-cancer activities [5], [6]. In the interest of the above suggestion, we have synthesized a new biologically active benzofuran- and thiazole-derivative, culminating in the discovery of N-(5-(2-bromobenzyl) thiazole-2-yl) benzofuran-2-carboxamide (Fig. 1).

One of the hallmarks of cancer cells including HCC cells is uncontrolled cell proliferation, which is mainly associated with cell cycle deregulation and escape of apoptosis by cancer cells. Especially, angiogenesis plays an important role in the progression in HCC. The presence of microvessels and the expression of vascular endothelial growth factor (VEGF) have been significantly involved in vascular invasion and tumor recurrence [7], [8]. Therefore, induction of cell cycle arrest and apoptosis by non-toxic compounds could be an effective strategy to check the uncontrolled cell proliferation and survival as well as inhibition of angiogenesis in cancer cells. In the present study, for the first time, we investigated the anti-cancer effect of HS-113, a novel compound and assessed its possibility as a chemotherapeutic agent against HCC.

Section snippets

Cells and materials

The human HCC cell lines Huh-7, Hep3B, and HepG2 were purchased from ATCC (Manassas, VA), and normal liver cell line HL-7702 was purchased from Sanghai Institute of Cell Biology (Sanghai, China). Huh-7 cells were cultured in Roswell Park Memorial Institute Media 1640 (RPMI-1640) and Hep3B and HepG2 cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM), supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. FBS, cell culture media, penicillin–streptomycin, and

HS-113 inhibited proliferation of HCC cells

We synthesized a novel compound HS-113, N-(5-(2-bromobenzyl) thiazol-2-yl) benzofuran-2-carboxamide (Fig. 1). Thus, to determine if HS-113 could function as a new therapeutic compound, we tested the cell growth inhibition on three HCC cell lines (HepG2, Hep3B, and Huh-7 cells). HCC cells were exposed to four concentrations from 0.1 to 20 μM of HS-113 for 48 h. Our result showed that cell growth was inhibited by HS-113 in a dose-dependent manner (Fig. 2A). Especially, HS-113 of 20 μM induced strong

Discussion

Recently, substantial effort has been dedicated to discover anticancer agents that can be applied to either cure primary tumor or prevent tumor relapse. Also, current interest is focusing on development of compounds with the potential beneficial effect without cytotoxicity to normal cells. Meanwhile, a lot of benzofuran and thiazole-derivatives showed anti-cancer effect by inhibiting cell proliferation and inducing apoptosis in various cancers cells including breast, pancreatic, and cervical

Conflict of interest

None declared.

Role of the funding source

None declared.

Acknowledgments

This work was supported by the Korean Health Technology R&D Project (A101185) and the National R&D Program for Cancer Control (1020250), Ministry of Health & Welfare, and National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF 2010-0011895, 0015340, and 0022179).

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