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Introduction
Cervical cancer is one of the most common malignant gynecological tumors in women worldwide. It is the third leading cause of cancer death among females in less developed countries (1). Concurrent radiotherapy with cisplatin-based chemotherapy plays a major role in treatment for early stage cervical cancer patients (2). However, patients who experience radiotherapy and concurrent chemoradiotherapy may also suffer from very strong adverse effects such as bowel obstruction, bleeding, urinary hematuria, or vaginal atrophy (3,4). Therefore, it is necessary to develop new drugs with less adverse effects for the treatment of cervical cancer.
Taraxerol is a triterpenoid compound, which has potent anti-inflammatory and anti-cancer activities. Taraxerol has effectively inhibited NADPH oxidase (NOS) activity in murine microglial cells (5). Our previous study found that taraxerol significantly inhibited lipopolysaccharide (LPS)- induced production of interleukin-1 (IL-1β), IL- 6, and tumor necrosis factor-alpha (TNF-α) by interfering with the activation of TAK1 and Akt, thus preventing NF-κB activation (6). It remarkably inhibited TPA-induced tumor promotion on mouse spontaneous mammary tumors (7). Taraxerol has shown in vitro cytotoxic activity against HepG2 and A431 human cancer cell lines and potent inhibition of topoisomerase II (8). Taraxerol are also known to augment the inhibitory effects of cyclooxygenases-1 and -2 by measuring prostaglandin E2 (PGE2) production, and induce quinone reductase in cultured Hepa1c1c7 mouse hepatoma cells (9). Many triterpenoids exhibit potent anti-cancer effects via the induction of apoptosis in tumor cells, including HeLa (10,12). Recently, it has been reported that taraxerol acetate induced apoptosis, autophagy, cell cycle arrest, and cell migration in human glioblastoma cells and a mouse xenograft model (13). However, whether taraxerol induced apoptosis and its underlying mechanisms of action is not clear. In this study, we have used a human cervical cancer cell line (HeLa) to assess the effects of taraxerol on a mitochondrial apoptotic pathway and determined the release of cytochrome c to the cytosol, and the activation of caspases and anti-poly (ADP-ribose) polymerase (PARP).
Materials and Methods Antibodies and reagents
3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide (MTT), dimethyl sulfoxide (DMSO), anti-Cox IV, anti-Bcl-2, anti-Bax, anti-cleaved caspase 3, anti-cleaved caspase 9, anti-cleaved caspase 8, PARP, anti-phospho-Akt (Ser473), anti-Akt antibodies and anti-cytochrome c were purchased from Cell Signaling Technology (Beverly, MA, USA). Anti-phospho-PI3K p85α (Tyr467), and anti-PI3K p85α antibodies were obtained from Santa...