A Novel Small-Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance

Zheng, Fei-Meng; Long, Zi; Hou, Zhi Jie; Luo, Yu; Xu, Ling; Xia, Jiang Long; Lai, Xiao Ju; Liu, Ji Wei; Wang, Xi; Kamran, Muhammad; Yan, Min; Shao, Shu Juan; Lam, Eric W.‐F.; Wang, Shao Wu; Lu, Gui; Liu, Quentin

doi:10.1158/1535-7163.mct-13-1029

Cited by 59 publications

(57 citation statements)

References 46 publications

(60 reference statements)

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“…Consistent with our recent finding that Aur-A inhibition increased the sensitivity of conventional chemotherapeutic drugs (17), previous studies indicated that Aur-A was critical for overriding cell cycle checkpoint in cancer, and therefore responsible for the chemoresistance (32,33). Aurora kinase inhibitor CCT129202 increased the sensitivity of ABCB1/ABCG2 overexpressing cells and cancer stem-like cells to chemotherapeutics (34).…”

Section: Discussionsupporting

confidence: 87%

“…AKI603, designed and synthesized by our lab (17,18), was dissolved in dimethyl sulfoxide (DMSO) to a stock concentration of 100 mM and stored at -20˚C. Imatinib (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in DMSO at 10 mM stock solution and stored at -20˚C.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we synthesized and identified a novel compound against Aur-A termed AKI603 with IC 50 =12.3±1.5 nM in vitro by kinase activity assay. AKI603 inhibited breast cancer cell line proliferation, especially abolished enrichment of tumor initiating cells (TICs) induced by epirubicin, suggesting its potent use in solid cancer treatment (17).…”

Section: Introductionmentioning

confidence: 99%

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A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

Long

Wang

Zheng

et al. 2015

International Journal of Oncology

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Abstract. Drug resistance still represents a major obstacle to successful chronic myeloid leukemia (CML) treatment and novel compounds or strategies to override this challenging problem are urgently required. Here, we evaluated a novel compound AKI603 against oncogenic Aurora kinase A (Aur-A) in imatinib-resistant CML cells. We found that Aur-A was highly activated in imatinib-resistant KBM5-T315I cells. AKI603 significantly inhibited the phosphorylation of Aur-A kinase at Thr288, while had little inhibitory effect on BCR-ABL kinase in both KBM5 and KBM5-T315I cells. AKI603 inhibited cell viability, and induced cell cycle arrest with polyploidy accumulation in KBM5 and KBM5-T315I cells. Moreover, inhibition of Aur-A kinase by AKI603 suppressed colony formation capacity without promoting obvious apoptosis. Importantly, AKI603 promoted cell differentiation in both CML cell types. Thus, our study suggested the potential clinical use of small molecule Aurora kinase inhibitor AKI603 to overcome imatinib resistance in CML treatment.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

Long

Wang

Zheng

et al. 2015

International Journal of Oncology

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“…Treatment strategies that combine surgery with adjuvant chemotherapy can improve survival but patients often eventually acquire resistance to chemotherapeutic agents [14, 15]. However, recent studies showed that trastuzumab-conjugated nanoparticles with simultaneous encapsulation of anti-miR-21 and 5-fluorouridine may boost the biological and clinical potential of cancer treatment [16].…”

Section: Introductionmentioning

confidence: 99%

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

Zhang¹,

Chen²,

Gong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: HER2 has been implicated in mammary tumorigenesis as well as aggressive tumor growth and metastasis. Its overexpression is related to a poor prognosis and chemoresistance in breast cancer patients. Although Grb2-associated binding protein 2 (Gab2) is important in the development and progression of human cancer, its effects and mechanisms in HER2-overexpressing breast cancer are unclear. Methods: Clone formation and MTT assays were used to examine cell proliferation. To detect the effect of Gab2 on the stemness of breast cancer cells, we used flow cytometry, a sphere formation assay, real-time PCR, and western blot. An animal model was created to validate the effect of Gab2 on tumor growth in vivo. Tissue slides were analyzed by immunohistochemistry. Results: Knockdown of Gab2 suppressed PI3K/AKT and MAPK/ERK pathway activity. Gab2 ablation also reduced the stemness of HER2-overexpressing breast cancer cells. In vivo, knockdown of Gab2 inhibited tumor growth. Conclusion: This study unveils a potential function of Gab2 in HER2-overexpressing breast cancer cells. Gab2 might be a potential target in the clinical therapy of HER2-overexpressing breast carcinoma.

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“…Esta quinase, além de ser um alvo de KRAS no pulmão envolvido em promover o fenótipo maligno (dos Santos et al, 2016), promove o fenótipo tronco-tumoral em outros tipos de neoplasia (Cammareri et al, 2010;Chefetz et al, 2011;Xia et al, 2013;Mannino et al, 2014;Zheng et al, 2014).…”

Section: Discussionunclassified

O papel da quinase Aurora A na biologia das células iniciadoras de turmor pulmonares com mutação em <i>KRAS</i>

Scalabrini¹

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2016 Ficha Catalográfica Elaborada pela Divisão de Biblioteca e Documentação do Conjunto das Químicas da USP.Scalab r ini, Luiza Co imb ra S2 8 1 p O papel da quinase Aurora A na biologia das células iniciadoras d e tumo r p ulmo nar es co m mutação em KRAS / Luiza Co imb ra Scalab r ini . --São P aulo , 201 6 . 110p. Dissertação (mestrado) -Instituto de Química da Universidade de São P aulo . Dep ar tamento d e B io q uímica.Or ientad o r : B assères, Daniela Sanchez 1. B io lo gia mo lecular 2. Câncer I. T . II. B assères, Daniela Sanchez , o r ientad o r. CDD Aos meus pais, sempre presentes,Maria Lúcia e Rogério. AGRADECIMENTOSA Deus, por me conduzir por todo o meu caminho e me dar forças para continuar nos momentos difíceis.À professora Dra. Daniela Bassères, que me recebeu tão bem em seu laboratório, assim como pelo incentivo na elaboração e desenvolvimento desse projeto, pelos ensinamentos e confiança diversas vezes depositada em mim.À Tatiana, pela colaboração na elaboração e desenvolvimento desse projeto, ademais aos diversos momentos de paciência e amizade dentro e fora do laboratório, como finais de semana divertidos e semanas de muito aprendizado. Aos amigos que Viçosa me presenteou, em especial a Isadora, Jamille e Larissa, que, mesmo de longe, fizeram parte dessa caminhada.À minha família e amigos de Belo Horizonte, que me recebem sempre com tanto carinho e sempre me apoiaram nas minhas jornadas longe de casa.Aos meus irmãos, Leo e Luana, pelo amor, carinho e amizade.Às minhas sobrinhas Mel e Alice, pela alegria que trouxe às nossa vidas.Por fim, mas não menos especiais, aos meus pais, Maria Lúcia e Rogério, pelo apoio incondicional para que eu siga em busca dos meus objetivos, por acreditarem em mim e serem meu exemplo de luta, família e amor. O cientista não é o homem que fornece as verdadeiras respostas; é quem faz as verdadeiras perguntas.Claude Lévi-Strauss Mutações ativadoras no gene KRAS são prevalentes em cancer de pulmão e a as vias de sinalização de RAS estão aumentadas em células iniciadoras de tumor (CITs), que são definidas como células autorrenováveis capazes de iniciar a formação tumoral, sustentar o crescimento tumoral e promover a disseminação tumoral. Entretanto, terapias direcionadas a RAS não foram efetivas até hoje e a identificação de alvos de KRAS que contribuam para o fenótipo oncogênico é necessária. Como a quinase Aurora A (AURKA) já foi implicada, tanto na oncogênese induzida por KRAS, quanto em promover a função das CITs, nós hipotetizamos que a inibição das vias de AURKA seria detrimental para a função de CITs pulmonares portadoras de KRAS oncogênica, desta forma diminuindo o comportamento maligno do câncer de pulmão. Para avaliar a função das CITs, nós usamos ensaios de crescimento de tumoresferas que permitem o crescimento seletivo de CITs in vitro. As linhagens pulmonares positivas para KRAS H358 e A549 formaram tumoresferas em cultura de baixa aderência e, quando comparadas às linhagens parentais, às células oriundas de tumoresferas apresentaram maior capacidade clon...

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A Novel Small-Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance

Cited by 59 publications

References 46 publications

A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

O papel da quinase Aurora A na biologia das células iniciadoras de turmor pulmonares com mutação em <i>KRAS</i>

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