ABSTRACT
PURPOSE: KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo. MATERIALS AND METHODS: The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. RESULTS: KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. CONCLUSION: KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.
Subject(s)
Animals , Mice , Aneuploidy , Breast Neoplasms , Cell Cycle , Cell Cycle Checkpoints , Cell Line , Fluorescent Antibody Technique , Heterografts , In Vitro Techniques , Microtubules , Mitosis , src-Family Kinases , Triple Negative Breast Neoplasms , Tubulin , Wound HealingABSTRACT
Microtubule inhibitor has been a hot area of anticancer drugs research.Microtubule inhibitor exert an anti-tumor effect by promoting or inhibiting the microtubule aggregation to break the dynamic balance of microtubule,hindering the spindle forma-tion of tumor cells,and then blocking the process of cell divi-sion.Mitotic catastrophe is a cell death phenomenon that is caused by abnormal cell division and damage of spindle structure in cell mitosis phase.In recent years more and more attention has been paid to mitotic catastrophe cell death because it has been confirmed clinically that microtubule inhibitors can induce mitotic catastrophe death of tumor cells.This paper reviews the latest research progress of microtubule inhibitors,and discusses the molecular mechanisms of mitotic catastrophe cell death tumor cells induced by microtubule inhibitors.
ABSTRACT
Objective Through gene reconstruction we generated pcDNA 3-survivin-mutant(Cys84Ala)plasmid, then the plasmid DNA was further transfected into gastric carcinoma cells by liposomal delivery. The effects of mutant survivin on cytokinetics of the gastric carcinoma cells were obversed. Methods By using immunohistochemical staining, the expression of survivin was detected in the gastric cancer tissues, and apoptosis was detected by flow cytometry. The PARP and cytochrome C expressions were determined by Western blot, the mitotic catastrophe was determined by immunofluorescence. Results Inhibition of survivin by mutant survivin cDNA could induce apoptosis, increase caspase-3 activity, cleave PARP and promote cytochrome C release in gastric cancer cells. Inhibition of survivin also caused mitotic catastrophe in gastric cancer cells. Conclusion Inhibition of survivin may induce apoptosis and mitotic catastrophe in gastric cancer. Survivin targeting gastric cancer therapy might be of potential benefit in the future.