| The incidence of lymphoma rose worldwide continuously in the past30years, and malignant lymphoma has become one of the prevalent tumors that threat human life and health. Although certain progress in anti-lymphoma predominantly mediated by chemotherapy has been achieved in the last30years; however, as a whole the long tem anti-lymphoma efficacy of currently used chemotherapeutics is still low and prone to produce serious complications, drug resistance, and relapse. The lack of potent and low toxic anti-lymphoma drugs has become a bottleneck to restrict the lymphoma treatment. Therefore, it is imperative to adopt new strategy and develop novel potent anti-lymphoma drugs.Cancer treatment by traditional Chinese medicinal herbal drugs has a long history and gain promising in certain cancer; whereas, the efficacy of the existed traditional Chinese herbal anti-cancer drugs need to be further improved. In recent years, we use modern science and technology to explore new anti-cancer drugs from the traditional Chinese medicinal herbal treasure house and utilized tumor models to test the anti-tumor activity of the120traditional Chinese medicinal herbs. For the first time, we found that Oroxin B exerted sound anti-lymphoma effect with very low toxicity. Oroxin B at lower doses effectively inhibited lymphoma cell growth, and very significantly reduced the tumorigenicity of the lymphoma cells, but not obviously affects the cell cycle and apoptosis. Apparently, the anti-lymphoma mechanisms of Oroxin B are different from the anti-cancer mechanisms of widely used traditional chemotherap eutics.Accordingly, we hypothesize that the anti-lymphoma of Orixin B may be through a new mechanism and performed a series of investigations. Cytological studies revealed that the lower dosages of Oroxin B significantly induced the enlargement of the cell size, occurrence of filopodia on the cell membrane, increment of vacuoles in the cytoplasm, and rich in cytoplasm, the appearance of catastrophic vacuolization of lymphoma cells, resulting in oncosis, a cell death mechanism distinct from induction of tumor cell apoptosis by traditional anti-cancer drugs. In addition, the molecular mechanism studies discovered that Oroxin B up-regulated expression of one of the mitogen-activated protein kinase (MAPK) kinases, MKK3, and activated it by an increase in phosphorylation of the MAPK kinase; next, activated MKK3specially activate a key kinases p38and down-stream signaling pathway in the cell stress-response system; following, activated P38promoted expression of an important tumor suppressor gene DNA-damage-inducible transcript3(DDIT3), also named as growth arrest and DNA damage-inducible protein (GADD153), and also called CCAAT/Enhancer-Binding Protein Homologous Protein-10(CHOP-10). DDIT3is the molecular marker of endoplasmic reticulum stress. The transcription factor DDIT3regulates the expression of many downstream effecter genes, promotes reticulum stress and immune response, inhibits cell growth, induce cell oncosis, apoptosis, and death, exerting anti-tumor effects. Additionally, Oroxin B also enhances expression of tumor suppressor gene p53which plays an important role in the inhibition of lymphoma.Taken together, this study reveals that Oroxin B selectively activates the stress-response system MKK3-P38-DDIT3pathway to induce lymphoma cell catastrophic vacuolization and oncosis. The research achievement has not been reported in the literatures so far, and is original, innovative and has Chinese characteristics, providing new research strategy and drug candidates for a new generation anti-lymphoma drugs. |
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