Maslinic acid potentiates the antitumor activities of gemcitabine in vitro and in vivo by inhibiting NF-κB-mediated survival signaling pathways in human gallbladder cancer cells

Abstract

Abstract. Gemcitabine (GEM) is one of the first-line drugs in the treatment of gallbladder cancer (GBC), although the therapeutic effect is not sustained due to resistance to the drug over time. Maslinic acid (MA) has been shown to inhibit transcription factor nuclear factor-κB (NF-κB), resulting in the suppression of survival signaling. The authors of the present study investigated whether MA enhanced the antitumor activity of GEM in GBC. Anti-proliferative effects of MA, GEM and MA + GEM were assessed using the MTT assay. Apoptosis was assessed using Annexin V and by western blot analysis of various mediators of apoptosis. Xenograft tumors of EH-GB2 GBC cells were established in athymic nude mice and were monitored following treatment with MA, GEM and MA + GEM. Immunohistochemistry of the tumors was used to examine various survival proteins. MA inhibited the in vitro proliferation of various GBC cell lines and potentiated the apoptosis and cell invasion inhibition induced by GEM. Western blot analysis showed that the combination of MA and GEM inhibited constitutive NF-κB activation and NF-κB-regulated gene products, including cyclin D1, Bcl-2, Bax, MMP-2 and MMP-9, to a greater extent. In vivo, the group that was treated with MA + GEM showed significant reductions in tumor volume and a decreased expression of NF-κB-regulated gene products. In conclusion, the results suggest that MA potentiates the antitumor effects of GEM in human GBC cell lines by suppressing the activation of NF-κB and its dowstream gene products, which are involved in survival signaling. IntroductionGallbladder cancer (GBC) is the most common cancer of the bile duct system and is the fifth most lethal cancer of the digestive system (1). The incidence of GBC in China, Thailand, Chile and Northern India is higher when compared with the United States and European countries (2). At present, radical surgical resection is the most effective treatment of GBC. However, for the majority of patients, surgery is not curative because of late detection and/or early, regional or distant metastasis. Additionally, few patients experience complete responses to chemotherapy, mainly due to chemoresistance. Thus, identifying novel approaches to enhance the antitumor effects of chemotherapeutic drugs and reduce chemoresistance are imperative.Maslinic acid (MA), a pentacyclic triterpene acid, is widely present in dietary plants, especially in olive fruit skins and hawthorn berries (3). The compound has attracted much interest due to its proven pharmacological safety and its many biological activities, including anticancer such as anti-inflammation (2), anti-viral (4,5), anti-oxidation (6), anti-diabetogenic (7), anticolonic cancer (8,9) and anti-astrocytoma (10) activities. MA has been shown to potentiate the anticancer activity of TNF-α in pancreatic cancer cells through the inhibition of nuclear factor-κB (NF-κB) survival signaling pathways (11).NF-κB is a transcriptional activator that has been extensively studied for its role in controlling the expression of...

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Maslinic Acid Enhances Docetaxel Response in Human Docetaxel-Resistant Triple Negative Breast Carcinoma MDA-MB-231 Cells via Regulating MELK-FoxM1-ABCB1 Signaling Cascade

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