The clinical efficiency of cisplatin against ovarian cancer is often limited by the development of drug resistance. In this work, we investigated PEGylated liposomal quercetin (Lipo-Que) on cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) human ovarian cancer models in vitro and in vivo to reveal whether a cisplatin-resistant ovarian cancer has susceptibility to quercetin (Que) and the mechanism of its antitumor activity. Lipo-Que was prepared using a solid dispersion method, and the obtained Lipo-Que is monodisperse with a mean diameter of 163 +/-10 nm. Besides, in vitro drug release assay showed a sustained release behavior of Lipo-Que. In vitro experiments suggested that Lipo-Que inhibited cell proliferation, induced apoptosis, and induced cell cycle arrest in both A2780s and A2780cp cells. Furthermore, antitumor activity of Lipo-Que was investigated in both cisplatin-sensitive and cisplatin-resistant human ovarian tumor xenograft models in nude mice. Lipo-Que significantly suppressed tumor growth in both models in comparison with free Que, blank liposomes (Lipo), or normal saline (NS). Furthermore, immunohistochemistry and immunofluorescence tests revealed that Lipo-Que induced apoptosis, decreased microvessel density, and inhibited proliferation of tumors in both A2780s and A2780cp tumor models. Therefore, our results suggest that Lipo-Que is an effective agent to inhibit tumor growth in both cisplatin-sensitive and cisplatin-resistant human ovarian cancers.
RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn’t. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.
Ovarian cancer is one of the most common carcinomas and causes lots of deaths in the world. Honokiol (HK), a natural product, was proved to be a potent anti-tumor agent, however the hydrophobicity of HK limited its application. In this work, we investigated the anti-tumor efficacy of honokiol nanoparticles (HK-NPs) and honokiol nanoparticles-loaded thermosensitive hydrogel (HK-NPs/hydrogel) on ovarian cancer in vitro and in vivo. HK-NPs with small particle size and high drug loading were prepared, and HK-NPs/hydrogel with a sol-gel transition temperature at about body temperature was also obtained. In addition, HK-NPs and HK-NPs/hydrogel showed a sustained release behavior of HK in vitro. HK-NPs could effectively inhibit proliferation of SKOV3 tumor cells in a dose-and time-dependent manner and induce apoptosis of tumor cells in vitro. Furthermore, compared with controlled groups, HK-NPs and HK-NPs/hydrogel dramatically inhibited growth of tumors and prolonged the survival of mice bearing ovarian peritoneal carcinomatosis (OPC), and the effects of HK-NPs/hydrogel were more obvious than HK-NPs (P , 0.05). Intraperitoneal chemotherapy with HK-NPs/hydrogel significantly inhibited proliferation activity and angiogenesis of tumors and increased apoptosis and necrosis in tumor tissues. Therefore, our results suggested that HK-NPs/hydrogel may have great potential in clinical applications in the treatment of OPC.
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