Inhibition of oleandrin on the proliferation and invasion of osteosarcoma cells in vitro by suppressing Wnt/[beta]-catenin signaling pathway
Author(s): Yunlong Ma1 , Bin Zhu1 , Xiaoguang Liu1 , Huilei Yu1 , Lei Yong1 , Xiao Liu1 , Jia Shao1 and Zhongjun Liu1
Osteosarcoma (OS) is a high-grade malignant bone tumor caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells with a high potential for local destruction and distant metastasis [1, 2]. OS mainly emerges in regions of active bone growth, such as the knee joint, lower femur and upper tibia, with a high incidence in adolescents. The treatment for OS, which combines surgery with neoadjuvant and adjuvant chemotherapy, has developed rapidly . Although the use of multi-drug chemotherapy has greatly increased the 5-year survival rate of patients, approximately 30 % of patients experience relapse or metastasis. Importantly, the 5-year survival rate of OS patients with pulmonary metastasis is extremely poor, at 10-20 % . Moreover, a variety of problems also exist with the current therapies, such as chemotherapy tolerance and side effects. This context limits the application of clinical chemotherapy drugs. Therefore, the identification a new drug with selective cytotoxicity to tumor cells is urgently needed.
Cardiac glycosides, a type of traditional drug that is used to treat cardiac insufficiency, were recently reported to have an antitumor effect on many tumor cells including breast cancer, lung cancer as well as leukemia [5-7]. Oleandrin is a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, which has been found to have anti-proliferative effects on tumor cells . The evidence indicates that oleandrin could be a perfect alternative substance due to its selective antitumor and chemoradiation sensitization properties . Moreover, oleandrin recently underwent a Phase I clinical trial as a novel drug for anticancer therapy in patients with refractory solid tumors .
There are some reports about the antitumor mechanisms of oleandrin. Cardiac glycosides, such as oleandrin, are known to inhibit the Na+ , K+ -ATPase pump, resulting in a consequent increase of calcium influx in the heart muscle . Previous studies reported that oleandrin inhibited the proliferation and induced the apoptosis of cells due to an increase in intracellular Ca2+ via the inhibition of Na+ , K+ -ATPase . Oleandrin inhibited the export of fibroblast growth factor-2 through membrane interactions and Na+ , K+ -ATPase activity in prostate cancer cells . Oleandrin also induced apoptosis in human leukemia cells through the dephosphorylation of Akt and expression of Fas L, as well as by altering the membrane fluidity . In addition, it suppressed the activation of NF-kB and induced Fas expression and autophagosome formation in tumor cells. The inhibition of Akt phosphorylation and the increase of MAPK expression were also demonstrated in response to oleandrin. The results of these studies have indicated an impending injury and the death of tumor cells following oleandrin treatment. However, no studies have described the antineoplastic activity of oleandrin on osteosarcoma cells and the related mechanisms.
Recent studies have reported the important effect of the Wnt/[beta]-catenin signaling pathway in tumorigenesis, bone development and...
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