Growth Inhibition and Apoptosis Induced by Osthole, A Natural Coumarin, in Hepatocellular Carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most commonly diagnosed tumors worldwide and is known to be resistant to conventional chemotherapy. New therapeutic strategies are urgently needed for treating HCC. Osthole, a natural coumarin derivative, has been shown to have anti-tumor activity. However, the effects of osthole on HCC have not yet been reported.Methods and FindingsHCC cell lines were treated with osthole at various concentrations for 24, 48 and 72 hours. The proliferations of the HCC cells were measured by MTT assays. Cell cycle distribution and apoptosis were determined by flow cytometry. HCC tumor models were established in mice by subcutaneously injection of SMMC-7721 or Hepa1-6 cells and the effect of osthole on tumor growths in vivo and the drug toxicity were studied. NF-κB activity after osthole treatment was determined by electrophoretic mobility shift assays and the expression of caspase-3 was measured by western blotting. The expression levels of other apoptosis-related genes were also determined by real-time PCR (PCR array) assays. Osthole displayed a dose- and time-dependent inhibition of the HCC cell proliferations in vitro. It also induced apoptosis and caused cell accumulation in G2 phase. Osthole could significantly suppress HCC tumor growth in vivo with no toxicity at the dose we used. NF-κB activity was significantly suppressed by osthole at the dose- and time-dependent manner. The cleaved caspase-3 was also increased by osthole treatment. The expression levels of some apoptosis-related genes that belong to TNF ligand family, TNF receptor family, Bcl-2 family, caspase family, TRAF family, death domain family, CIDE domain and death effector domain family and CARD family were all increased with osthole treatment.ConclusionOsthole could significantly inhibit HCC growth in vitro and in vivo through cell cycle arrest and inducing apoptosis by suppressing NF-κB activity and promoting the expressions of apoptosis-related genes.

Osthole Exhibits Anti-Cancer Property in Rat Glioma Cells Through Inhibiting PI3K/Akt and MAPK Signaling Pathways

“…All these results showed that Osthole promoted the obvious apoptosis in C6 cells. These data were consistent with the previous studies which Osthole induced apoptosis in cancer cells from different types of tissue [16,23]. …”

“…Amounts of studies showed that Osthole regulates cell apoptosis, proliferation and invasion via multiple signaling pathways in many cancer cells [13,15,16]. In addition, it has been reported in recent studies that Osthole has essential roles in brain functions by protecting neurons [17,18,19,20,21], suggesting that Osthole could penetrate the blood-brain barrier for the chemotherapy drugs of brain tumours.…”

Osthole Induces Cell Cycle Arrest and Inhibits Migration and Invasion via PTEN/Akt Pathways in Osteosarcoma

“…Osthole has been shown to exert a wide variety of biological effects, such as anti-seizure, anti-osteoporosis and anti-inflammation [10,11,12,13]. It has been well documented that osthole inhibits the growth and proliferation of various cancer cells through inducing apoptosis or cell cycle arrest [14,15]. Moreover, osthole derivative NBM-T-BMX-OS01 sensitizes A549 cells to cisplatin [16].…”

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

“…Natural coumarins, such as osthole (Zhang et al, 2012), esculetin (Lee et al, 2013), and umbelliferone (Weber et al, 1998) as well as several coumarin containing plant extracts, have been reported to inhibit the growth of cancer cells (Li et al, 2013;Ngo et al, 2010).…”