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, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/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 β-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.
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This work was performed within the framework of COST Action CA17104 STRATAGEM -” New diagnostic and therapeutic tools against multidrug resistant tumors”.
The work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. III41031), the EU Research Potential (FP7-REGPOT- 2012-CT2012–31637-IMBRAIN), and the European Social Fund under the Global Grant measure (Grant No. VP1–3.1-ŠMM-07-K-01-002).We thank the Spanish Government for financial support through project PGC2018-094503-B-C22 (MCIU/AEI/FEDER, UE).
Conflict of interest
Jelena Dinić declares that she has no conflict of interest. Carla Ríos-Luci declares that she has no conflict of interest. Ieva Karpaviciene declares that she has no conflict of interest. Inga Cikotiene declares that she has no conflict of interest. Miguel X. Fernandes declares that he has no conflict of interest. Milica Pešić declares that she has no conflict of interest. José M. Padrón declares that he has no conflict of interest.
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Dinić, J., Ríos-Luci, C., Karpaviciene, I. et al. CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells. Invest New Drugs 38, 584–598 (2020). https://doi.org/10.1007/s10637-019-00803-6
- α-Branched α,β-unsaturated ketones
- Anticancer activity
- Microtubule targeting agents
- Multidrug resistance