Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.
- Author:
Seongyeong KIM
1
;
Ahrum MIN
;
Kyung Hun LEE
;
Yaewon YANG
;
Tae Yong KIM
;
Jee Min LIM
;
So Jung PARK
;
Hyun Jin NAM
;
Jung Eun KIM
;
Sang Hyun SONG
;
Sae Won HAN
;
Do Youn OH
;
Jee Hyun KIM
;
Tae You KIM
;
David HANGAUER
;
Johnson Yiu Nam LAU
;
Kyongok IM
;
Dong Soon LEE
;
Yung Jue BANG
;
Seock Ah IM
Author Information
- Publication Type:Original Article
- Keywords: Src kinase inhibitor; Mitotic catastrophe; Microtubules; KX-01; Triple negative breast neoplasms
- MeSH: Aneuploidy; Animals; Breast Neoplasms; Cell Cycle; Cell Cycle Checkpoints; Cell Line; Fluorescent Antibody Technique; Heterografts; In Vitro Techniques; Mice; Microtubules; Mitosis*; src-Family Kinases*; Triple Negative Breast Neoplasms; Tubulin; Wound Healing
- From:Cancer Research and Treatment 2017;49(3):643-655
- CountryRepublic of Korea
- Language:English
- 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.
