CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells
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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.
Keywordsα-Branched α,β-unsaturated ketones Anticancer activity β-Tubulin Microtubule targeting agents Multidrug resistance
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).
Compliance with ethical standards
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.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study, formal consent is not required.
- 1.Zhou J, Giannakakou P (2005) Targeting microtubules for cancer chemotherapy. Curr Med Chem Anticancer Agents 5(1):65–71Google Scholar
- 5.Riordan JR, Ling V (1985) Genetic and biochemical characterization of multidrug resistance. Pharmacol Ther 28(1):51–75Google Scholar
- 8.Gonzalez-Garay ML, Chang L, Blade K, Menick DR, Cabral F (1999) A beta-tubulin leucine cluster involved in microtubule assembly and paclitaxel resistance. J Biol Chem 274(34):23875–23882Google Scholar
- 9.Kavallaris M, Tait AS, Walsh BJ, He L, Horwitz SB, Norris MD, Haber M (2001) Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells. Cancer Res 61(15):5803–5809Google Scholar
- 10.Giannakakou P, Gussio R, Nogales E, Downing KH, Zaharevitz D, Bollbuck B, Poy G, Sackett D, Nicolaou KC, Fojo T (2000) A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci U S A 97(6):2904–2909. https://doi.org/10.1073/pnas.040546297 Google Scholar
- 15.Podolski-Renic A, Bankovic J, Dinic J, Rios-Luci C, Fernandes MX, Ortega N, Kovacevic-Grujicic N, Martin VS, Padron JM, Pesic M (2017) DTA0100, dual topoisomerase II and microtubule inhibitor, evades paclitaxel resistance in P-glycoprotein overexpressing cancer cells. European Journal of Pharmaceutical Sciences: Eur J Pharm Sci 105:159–168. https://doi.org/10.1016/j.ejps.2017.05.011
- 16.Zhang CC, Yang JM, Bash-Babula J, White E, Murphy M, Levine AJ, Hait WN (1999) DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4. Cancer Res 59(15):3663–3670Google Scholar
- 21.Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254Google Scholar
- 26.Michel L, Diaz-Rodriguez E, Narayan G, Hernando E, Murty VV, Benezra R (2004) Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci U S A 101(13):4459–4464. https://doi.org/10.1073/pnas.0306069101 Google Scholar
- 31.Israels ED, Israels LG (2000) The cell cycle. Oncologist 5(6):510–513Google Scholar
- 34.Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273(16):9357–9360Google Scholar
- 37.Jordan MA, Thrower D, Wilson L (1992) Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. Implications for the role of microtubule dynamics in mitosis. J Cell Sci 102(Pt 3):401–416Google Scholar
- 38.Xu K, Schwarz PM, Ludueña RF (2002) Interaction of nocodazole with tubulin isotypes. Drug Dev Res 55(2):91–96Google Scholar
- 39.Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A, Auer G, Ried T (2000) Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosom Cancer 27(2):183–190Google Scholar
- 40.Tsushimi T, Noshima S, Oga A, Esato K, Sasaki K (2001) DNA amplification and chromosomal translocations are accompanied by chromosomal instability: analysis of seven human colon cancer cell lines by comparative genomic hybridization and spectral karyotyping. Cancer Genet Cytogenet 126(1):34–38Google Scholar
- 41.Podolski-Renic A, Jadranin M, Stankovic T, Bankovic J, Stojkovic S, Chiourea M, Aljancic I, Vajs V, Tesevic V, Ruzdijic S, Gagos S, Tanic N, Pesic M (2013) Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing. Cancer Chemother Pharmacol 72(3):683–697. https://doi.org/10.1007/s00280-013-2247-1 Google Scholar
- 42.Chen Y, Simon SM (2000) In situ biochemical demonstration that P-glycoprotein is a drug efflux pump with broad specificity. J Cell Biol 148(5):863–870Google Scholar
- 46.Risinger AL, Jackson EM, Polin LA, Helms GL, LeBoeuf DA, Joe PA, Hopper-Borge E, Luduena RF, Kruh GD, Mooberry SL (2008) The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms. Cancer Res 68(21):8881–8888. https://doi.org/10.1158/0008-5472.CAN-08-2037 Google Scholar