br Introduction Human esophageal carcinoma
Introduction Human esophageal carcinoma is one of the most frequently diagnosed cancers, ranked as the eighth leading causes of cancer-related mortality worldwide. Esophagus squamous cell carcinoma (ESCC) is the most common histological type of esophageal carcinomas, especially with a higher incidence in developing nations (Abnet et al., 2017, Rustgi and El-Serag, 2014). Epidemiological studies have demonstrated that alcohol consumption and tobacco use are closely linked to increased ESCC risk. ESCC is notoriously aggressive in nature, spreading by a variety of pathways including direct extension, lymphatic spread and hematogenous metastasis (Abnet et al., 2017, Lagergren and Lagergren, 2013, Liang et al., 2017). Despite advances in early detection and standard treatment, ESCC is often diagnosed at an advanced stage and has a poor prognosis. The overall 5-year survival rate for late stage ESCC is <15%, which has hardly improved during the past few decades (Liang et al., 2017). The underlying reasons for this disappointingly low survival rate remain to be greatly elucidated. Therefore, a better understanding of the molecular mechanisms of ESCC pathogenesis or identifies a novel chemical entity with activity against ESCC is expected to facilitate the development of novel therapies that can complement current traditionally therapeutic methods. The Aurora kinases, a closely related subgroup of 3 serine/threonine kinases, including Aurora A, B, and C, are believed to play a key role in protein phosphorylation in mitosis and have been shown to contribute to the development and progression of cancer (Nguyen and Schindler, 2017, Tang et al., 2017). Aurora B is localized to the centromeres from the prophase to the metaphase-anaphase transition. Thereafter, it is localized to midzone spindle microtubules during the telophase and subsequently to midbody during cytokinesis. Small-molecule inhibitors and siRNA of Aurora B abrogate the mitotic-spindle checkpoint and cause premature mitotic exit without the completion of cytokinesis, leading to 4N DNA-containing cells that continue to progress through the thapsigargin receptor (Carmena et al., 2009, Krenn and Musacchio, 2015, Liu et al., 2009). In malignancy, alterations of Aurora kinase have been linked with genetic instability, including mitotic errors, chromosomal aneuploidy, deregulation of cell proliferation and apoptosis, which are highly associated with tumorigenesis (Mahadevan et al., 2017, Portella et al., 2011, Schecher et al., 2017). Aurora B is overexpressed in many tumor types and has been linked to poor patient prognosis in cancers (Lens et al., 2010, Otto and Sicinski, 2017). Recently, several Aurora B inhibitors have been developed, including AZD1152, BI 811283, ZM447439, and VX-680, etc., the clinical trial data demonstrated that inhibition of Aurora B kinase displayed a generally manageable safety profile and disease stabilization in some patients (Bavetsias and Linardopoulos, 2015, Falchook et al., 2015, Tang et al., 2017, Yan et al., 2016, Ziemska and Solecka, 2016). In the present study, we identified a natural compound, deguelin, which was isolated from the Legume family, Lonchocarpus, Derris, or Tephrosia, as an effective Aurora B inhibitor for using in ESCC therapy. We investigated the therapeutic effect of deguelin in ESCC both in vitro and in vivo. Our results could provide an option for clinical targeting anti-mitotic therapies of ESCC.
Materials and Methods
Discussion Abnormal activation of mitosis plays a crucial role in the process of human tumorigenesis. In the past few decades, targeting anti-mitotic therapies is a highly successful strategy for human anticancer treatment. Microtubule dynamics targeted agents, including the vinca alkaloids and taxanes, are highly active against a variety of human cancer types. However, development of drug resistance and highly toxic to normal dividing cells remain persistent problems (Hardin et al., 2017, Kavallaris, 2010, Louage et al., 2017). Therefore, identification of novel nonmicrotubule proteins therapeutic targets is still an urgent demand for anticancer treatment. Recently, the Aurora kinases have gained prominence as essential regulators of somatic cell division. Aurora B kinase is essential for chromosome condensation, kinetochore function, cytokinesis, and the proper function of the spindle assembly checkpoint when spindle tension is perturbed. Aurora B was first demonstrated to be overexpressed in colon cancer in 1998 (Bischoff et al., 1998). Cumulative evidence indicated that the amplification/overexpression and/or hyperactivation of Aurora B kinase is a frequent finding in a panel of human malignancies, such as breast (Larsen et al., 2015, Zhang et al., 2015), liver (Liu et al., 2017), lung (Al-Khafaji et al., 2017, Helfrich et al., 2016), prostate (Schecher et al., 2017, Zekri et al., 2017) cancer and leukemia (Floc'h et al., 2017, Song et al., 2017). The evidence linking Aurora B overexpression and malignancy has generated significant interest in the development of small-molecule inhibitors against this protein.