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Antitumor effect of KX-01, a novel Src and tubulin inhibitor, in triple negative breast cancer cells : 삼중음성유방암 세포주에서 Src과 tubulin을 동시에 억제하는 KX-01의 항종양효과 연구

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Authors

김선경

Advisor
임 석아
Major
의과대학 협동과정 종양생물학전공
Issue Date
2014-08
Publisher
서울대학교 대학원
Keywords
Src inhibitorTubulin inhibitorTriple negative breast cancerMitotic catastrophe
Description
학위논문 (석사)-- 서울대학교 대학원 : 협동과정 종양생물학전공, 2014. 8. 임석아.
Abstract
Background: Src kinases have been involved in cell proliferation, invasion, and metastasis and is one of the highly expressed oncogenes in breast cancer. Therefore, it could be a reasonable target for therapeutic strategy. Although several Src inhibitors, targeting the ATP binding site, were developed, none of them have shown remarkable responses as monotherapeutic agents in breast cancer clinical trials. KX-01 (KX2-391) is a novel peptidomimetic agent, and a non ATP-competitive Src inhibitor, which has potent efficacy for inhibiting both Src as well as tubulin polymerization. Its dual inhibition effects could potentially overcome the limitations of the Src inhibitors that have been evaluated previously.
Materials & Methods: To determine the antitumor effect of KX-01, MTT assay was performed to test cytotoxic effect of KX-01 on breast cancer cell lines. Then, through flow cytometry assay, cell cycle changes and aneuploidy population changes were examined after KX-01 treatment. Migration inhibitory effect was examined by wound healing assay and expression of protein molecular level changes by KX-01 treatment was verified by western blotting. The microtubule polymerization inhibitory effect was checked by immunofluorescence assay. Mouse xenograft model bearing MDA-MB-231 tumor was used to demonstrate in vivo effect of KX-01.
Results: KX-01 effectively inhibited cell growth in most breast cancer cells including ER/PR/HER2 negative breast cancer cells. KX-01 down-regulates the phospho-Src expre- ssion. Phosphorylated FAK, ERK, AKT and STAT3 were also down-regulated by KX-01 treatment in MDA-MB-231, -468 and BT-549 cells. By wound healing assay, migration inhibitory effect of KX-01 was confirmed in BT-549 cells. Increase of G2/M cell cycle arrest was observed in KX-01 sensitive cell lines by dose dependent manner. In addition, increased multi-nucleated cells were observed along with the elevated aneuploidy levels in KX-01 sensitive cell lines indicating that mitotic catastrophes could be induced by KX-01 treatment. The in vivo data also showed that delay of tumor growth in MDA-MB-231 mouse xenograft model.
Conclusion: Inhibition of cell growth and migration, as well as an induction of mitotic catastrophe, were observed in triple negative breast cancer cell lines treated with KX-01. Moreover, using mouse xenograft model, I confirm antitumor effect of KX-01 in vivo. Our data strongly supports utilizing KX-01 as a new therapeutic agents for treating triple negative breast cancer.
Language
English
URI
https://hdl.handle.net/10371/132295
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