icaritin and Lung-Neoplasms

Bone metastasis is one of the common phenomena in the late stage of lung cancer. Inhibition of bone metastasis can improve the survival of lung cancer patients. However, the current drugs for the treatment of bone metastasis have shown little effect on overall survival. Therefore, there is an urgent necessity to identify novel drugs capable of preventing and treating bone metastasis of lung cancer. Our study determined that icaritin (ICT) can inhibit lung cancer-mediated osteoclastogenesis and induce the apoptosis of osteoclasts. Exposure to ICT increased the activation of adenosine 5'-monophosphate-activated protein kinase (AMPK), reduced the activation of mammalian target of rapamycin (mTOR) and decreased the expression of bcl-2. The bioactivity of ICT on osteoclastogenesis was associated with the regulation of the AMPK/mTOR signaling pathway. Blocking AMPK significantly increased osteoclast differentiation, decreased osteoclast apoptosis and canceled the effects of ICT on the phosphorylation of AMPK as well as the inhibition of mTOR and bcl-2. Furthermore, ICT decreased the levels of IL-6 and TNF-α in osteoclasts, while the AMPK inhibitor compound C significantly abolished the inhibitory effects of ICT on IL-6 and TNF-α. Thus, the present study demonstrated that ICT may be a potential natural agent for the treatment of bone metastasis in patients with lung cancer.

Topics: A549 Cells; AMP-Activated Protein Kinases; Animals; Apoptosis; Flavonoids; Humans; Interleukin-6; Lung Neoplasms; Mice; Osteoclasts; Osteogenesis; RAW 264.7 Cells; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Icaritin, a prenylflavonoid derivative from Epimedium Genus, has been reported to exhibit tumor inhibitory effects on many types of tumor cells. Numerous studies have demonstrated that microRNAs (miRs) involve in the biological process of carcinogenesis by controlling expression of their target mRNAs to facilitate tumor growth, invasion, angiogenesis, and immune evasion. miR-124 was reported to involve in the icaritin-induced mitochondrial apoptosis in human carcinoma cells. However, the roles of other miRs in the anti-tumor effects of icaritin and its underlying mechanisms still need to be elucidated. In the present study, realtime-PCR results showed that miR-10a was significantly down-regulated after icaritin treatment in human non-small cell lung cancer cells (A549). Over-expression of miR-10a in A549 cells dramatically abrogated the anti-tumor effects of icaritin on cell proliferation, apoptosis, migration, while suppression of miR-10a partially reproduced the anti-tumor effects of icaritin. Furthermore, we found that the regulation of miR-10a in the anti-tumor effects of icaritin was mediated via the PTEN/AKT/ERK pathway by directly targeting to PTEN. Taken together, miR-10a targets PTEN to mediate the anti-tumor effect of icaritin in A549 cells, which provides a novel insight into the anti-tumor mechanism of icaritin and may provide a new strategy for lung cancer therapy.

Topics: A549 Cells; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Flavonoids; Humans; Lung Neoplasms; Membrane Glycoproteins; MicroRNAs; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Immunologic; Signal Transduction

Lung cancer is the leading cause of cancer-related death in both men and women. Lung cancer contains a small population of cancer cells with stem-like features known as cancer stem cells (CSCs). CSCs are often more resistant to current therapeutic treatments. Thus, it is urgent to develop a novel agent that is able to inhibit CSCs growth. In this study, we examined the ability of SNG1153, a novel chemical agent to inhibit the growth of lung CSCs. We found that SNG1153 inhibited growth and induced apoptosis in established lung cancer cells. We also found that SNG1153 inhibited the tumorsphere formation and decreased CD133-positive (lung CSC marker) cancer cells. SNG1153 was able to attenuate tumor formation in NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice injected with lung tumorsphere cells. We further demonstrated that SNG1153 induced β-catenin phosphorylation and down-regulated β-catenin. Our results thus demonstrate that SNG1153 effectively inhibits the growth of lung CSCs and suggest that SNG1153 may be a novel therapeutic agent to treat human lung cancer.

Topics: Animals; Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Cell Proliferation; Chromans; Epimedium; Flavonoids; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Neoplastic Stem Cells; Xenograft Model Antitumor Assays

Icaritin, a prenylflavonoid derivative from Epimedium Genus, has been shown to exhibit many pharmacological and biological activities. However, the function and the underlying mechanisms of icaritin in human non-small cell lung cancer have not been fully elucidated. The purpose of this study was to investigate the anticancer effects of icaritin on A549 cells and explore the underlying molecular mechanism. The cell viability after icaritin treatment was tested by MTT assay. The cell cycle distribution, apoptosis and reactive oxygen species (ROS) levels were analyzed by flow cytometry. The mRNA and protein expression levels of the genes involved in proliferation and apoptosis were respectively detected by RT-PCR and Western blotting. The results demonstrated that icaritin induced cell cycle arrest at S phase, and down-regulated the expression levels of S regulatory proteins such as Cyclin A and CDK2. Icaritin also induced cell apoptosis characterized by positive Hoechst 33258 staining, accumulation of the Annexin V-positive cells, increased ROS level and alteration in Bcl-2 family proteins expression. Moreover, icaritin induced sustained phosphorylation of ERK and p38 MAPK. These findings suggested that icaritin might be a new potent inhibitor by inducing S phase arrest and apoptosis in human lung carcinoma A549 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Flavonoids; Humans; Lung Neoplasms; MAP Kinase Signaling System; Neoplasm Proteins; Reactive Oxygen Species; S Phase Cell Cycle Checkpoints