共 50 条
CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells
被引:5
|作者:
Dinic, Jelena
[1
]
Rios-Luci, Carla
[2
]
Karpaviciene, Ieva
[3
]
Cikotiene, Inga
[3
]
Fernandes, Miguel X.
[2
]
Pesic, Milica
[1
]
Padron, Jose M.
[2
]
机构:
[1] Univ Belgrade, Inst Biol Res Sinisa Stankovi, Bulevar Despota Stefana 142, Belgrade 11060, Serbia
[2] Univ La Laguna, Inst Univ Bioorgan Antonio Gonzalez IUBO AG, Ctr Invest Biomed Canarias CIBICAN, BioLab, C Astrofis Avda Astrofis Francisco Sanchez 2, Tenerife 38206, Spain
[3] Vilnius Univ, Fac Chem, Dept Organ Chem, Naugarduko 24, LT-03225 Vilnius, Lithuania
关键词:
alpha-Branched alpha;
beta-unsaturated ketones;
Anticancer activity;
beta-Tubulin;
Microtubule targeting agents;
Multidrug resistance;
P-GLYCOPROTEIN;
VINCA ALKALOIDS;
TUBULIN;
EXPRESSION;
TAXANES;
AMPLIFICATION;
SENSITIVITY;
INSTABILITY;
NOCODAZOLE;
INHIBITION;
D O I:
10.1007/s10637-019-00803-6
中图分类号:
R73 [肿瘤学];
学科分类号:
100214 ;
摘要:
Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, alpha-branched alpha,beta-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G(2)/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of beta-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.
引用
收藏
页码:584 / 598
页数:15
相关论文