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
共 50 条
  • [41] Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity
    Bao, Bin
    Mitrea, Cristina
    Wijesinghe, Priyanga
    Marchetti, Luca
    Girsch, Emily
    Farr, Rebecca L.
    Boerner, Julie L.
    Mohammad, Ramzi
    Dyson, Greg
    Terlecky, Stanley R.
    Bollig-Fischer, Aliccia
    SCIENTIFIC REPORTS, 2017, 7
  • [42] Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance
    Hsieh, Yao-Yu
    Du, Jia-Ling
    Yang, Pei-Ming
    MOLECULAR ONCOLOGY, 2024, 18 (02) : 386 - 414
  • [43] Stiffening of DU145 prostate cancer cells driven by actin filaments - microtubule crosstalk conferring resistance to microtubule-targeting drugs
    Kubiak, Andrzej
    Chighizola, Matteo
    Schulte, Carsten
    Bryniarska, Natalia
    Wesolowska, Julita
    Pudelek, Maciej
    Lasota, Malgorzata
    Ryszawy, Damian
    Basta-Kaim, Agnieszka
    Laidler, Piotr
    Podesta, Alessandro
    Lekka, Malgorzata
    NANOSCALE, 2021, 13 (12) : 6212 - 6226
  • [44] Inhibition of the notch signaling pathway overcomes resistance of cervical cancer cells to paclitaxel through retardation of the epithelial-mesenchymal transition process
    Sun, Tianzhu
    Zhang, Dengyang
    Wang, Zehao
    Zhao, Bingyu
    Li, Yaping
    Sun, Xiuli
    Liu, Jia
    Wang, Xuanjun
    Sheng, Jun
    ENVIRONMENTAL TOXICOLOGY, 2021, 36 (09) : 1758 - 1764
  • [45] Dietary agent induced AMPK activation: Targeting stem cells for the prevention of colon cancer
    Kwatra, Deep
    Venugopal, Anand
    Subramaniam, Dharmalingam
    Anant, Shrikant
    CANCER RESEARCH, 2012, 72
  • [46] KRT17 confers paclitaxel-induced resistance and migration to cervical cancer cells
    L, Jinyuan
    Chen, Qiufang
    Deng, Zhendong
    Chen, Xiaoting
    Liu, Hong
    Tao, Ying
    Wang, Xiaoyu
    Lin, Shaoqiang
    Liu, Naihua
    LIFE SCIENCES, 2019, 224 : 255 - 262
  • [47] Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib
    Jeong, Yun-Ji
    Kang, Jong Soon
    Lee, Su In
    Son, Dong Min
    Yun, Jieun
    Baek, Ji Young
    Kim, Sang Kyum
    Lee, Kiho
    Park, Song-Kyu
    ONCOLOGY LETTERS, 2016, 12 (03) : 2153 - 2158
  • [48] Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model
    Nguyen, H. G.
    Yang, J. C.
    Kung, H-J
    Shi, X-B
    Tilki, D.
    Lara, P. N., Jr.
    White, R. W. DeVere
    Gao, A. C.
    Evans, C. P.
    ONCOGENE, 2014, 33 (36) : 4521 - 4530
  • [49] Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model
    H G Nguyen
    J C Yang
    H-J Kung
    X-B Shi
    D Tilki
    P N Lara
    R W DeVere White
    A C Gao
    C P Evans
    Oncogene, 2014, 33 : 4521 - 4530
  • [50] Targeting autophagy overcomes enzalutamide resistance in castrate-resistant prostate cancer cells and improves therapeutic response in a xenograft model
    Yang, Joy C.
    Nguyen, Hao G.
    Kung, Hsing-Jien
    Shi, Xu-Bao
    Tilki, Derya
    White, Ralph W. deVere
    Gao, Allen C.
    Evans, Christopher P.
    CANCER RESEARCH, 2014, 74 (19)