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CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells

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Summary

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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References

  1. Zhou J, Giannakakou P (2005) Targeting microtubules for cancer chemotherapy. Curr Med Chem Anticancer Agents 5(1):65–71

    Article  CAS  Google Scholar 

  2. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265. https://doi.org/10.1038/nrc1317

    Article  CAS  PubMed  Google Scholar 

  3. Downing KH (2000) Structural basis for the interaction of tubulin with proteins and drugs that affect microtubule dynamics. Annu Rev Cell Dev Biol 16:89–111. https://doi.org/10.1146/annurev.cellbio.16.1.89

    Article  CAS  PubMed  Google Scholar 

  4. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2(1):48–58. https://doi.org/10.1038/nrc706

    Article  CAS  PubMed  Google Scholar 

  5. Riordan JR, Ling V (1985) Genetic and biochemical characterization of multidrug resistance. Pharmacol Ther 28(1):51–75

    Article  CAS  Google Scholar 

  6. Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9(1):105–127. https://doi.org/10.2217/14622416.9.1.105

    Article  CAS  PubMed  Google Scholar 

  7. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398. https://doi.org/10.1146/annurev.pharmtox.39.1.361

    Article  CAS  PubMed  Google 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):23875–23882

    Article  CAS  Google 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):5803–5809

    CAS  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ganapathi RN, Ganapathi MK (2013) Mechanisms regulating resistance to inhibitors of topoisomerase II. Front Pharmacol 4:89. https://doi.org/10.3389/fphar.2013.00089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McGrogan BT, Gilmartin B, Carney DN, McCann A (2008) Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta 1785(2):96–132. https://doi.org/10.1016/j.bbcan.2007.10.004

    Article  CAS  PubMed  Google Scholar 

  13. Goncalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, Wilson L, Jordan MA (2001) Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci U S A 98(20):11737–11742. https://doi.org/10.1073/pnas.191388598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kavallaris M, Kuo DY, Burkhart CA, Regl DL, Norris MD, Haber M, Horwitz SB (1997) Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest 100(5):1282–1293. https://doi.org/10.1172/JCI119642

    Article  CAS  PubMed  PubMed Central  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):3663–3670

    CAS  PubMed  Google Scholar 

  17. Zhang CC, Yang JM, White E, Murphy M, Levine A, Hait WN (1998) The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells. Oncogene 16(12):1617–1624. https://doi.org/10.1038/sj.onc.1201658

    Article  CAS  PubMed  Google Scholar 

  18. Karpaviciene I, Cikotiene I, Padron JM (2013) Synthesis and antiproliferative activity of alpha-branched alpha,beta-unsaturated ketones. Eur J Med Chem 70:568–578. https://doi.org/10.1016/j.ejmech.2013.10.041

    Article  CAS  PubMed  Google Scholar 

  19. Podolski-Renic A, Andelkovic T, Bankovic J, Tanic N, Ruzdijic S, Pesic M (2011) The role of paclitaxel in the development and treatment of multidrug resistant cancer cell lines. Biomed Pharmacother 65(5):345–353. https://doi.org/10.1016/j.biopha.2011.04.015

    Article  CAS  PubMed  Google Scholar 

  20. Kepp O, Galluzzi L, Lipinski M, Yuan J, Kroemer G (2011) Cell death assays for drug discovery. Nat Rev Drug Discov 10(3):221–237. https://doi.org/10.1038/nrd3373

    Article  CAS  PubMed  Google 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 72:248–254

    Article  CAS  Google Scholar 

  22. Gascoigne KE, Taylor SS (2008) Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14(2):111–122. https://doi.org/10.1016/j.ccr.2008.07.002

    Article  CAS  PubMed  Google Scholar 

  23. Rieder CL, Maiato H (2004) Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 7(5):637–651. https://doi.org/10.1016/j.devcel.2004.09.002

    Article  CAS  PubMed  Google Scholar 

  24. Nakano H, Wang W, Hashizume C, Funasaka T, Sato H, Wong RW (2011) Unexpected role of nucleoporins in coordination of cell cycle progression. Cell Cycle 10(3):425–433. https://doi.org/10.4161/cc.10.3.14721

    Article  CAS  PubMed  Google Scholar 

  25. Fernandez-Martinez J, Rout MP (2009) Nuclear pore complex biogenesis. Curr Opin Cell Biol 21(4):603–612. https://doi.org/10.1016/j.ceb.2009.05.001

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Decordier I, Cundari E, Kirsch-Volders M (2008) Mitotic checkpoints and the maintenance of the chromosome karyotype. Mutat Res 651(1–2):3–13. https://doi.org/10.1016/j.mrgentox.2007.10.020

    Article  CAS  PubMed  Google Scholar 

  28. Lampson MA, Kapoor TM (2005) The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat Cell Biol 7(1):93–98. https://doi.org/10.1038/ncb1208

    Article  CAS  PubMed  Google Scholar 

  29. Sudakin V, Chan GK, Yen TJ (2001) Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154(5):925–936. https://doi.org/10.1083/jcb.200102093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dalton WB, Yang VW (2009) Role of prolonged mitotic checkpoint activation in the formation and treatment of cancer. Future Oncol 5(9):1363–1370. https://doi.org/10.2217/fon.09.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Israels ED, Israels LG (2000) The cell cycle. Oncologist 5(6):510–513

    Article  CAS  Google Scholar 

  32. Harvey SL, Charlet A, Haas W, Gygi SP, Kellogg DR (2005) Cdk1-dependent regulation of the mitotic inhibitor Wee1. Cell 122(3):407–420. https://doi.org/10.1016/j.cell.2005.05.029

    Article  CAS  PubMed  Google Scholar 

  33. Blagosklonny MV (2007) Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events. Cell Cycle 6(1):70–74. https://doi.org/10.4161/cc.6.1.3682

    Article  CAS  PubMed  Google 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):9357–9360

    Article  CAS  Google Scholar 

  35. Walensky LD (2006) BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ 13(8):1339–1350. https://doi.org/10.1038/sj.cdd.4401992

    Article  CAS  PubMed  Google Scholar 

  36. Stanton RA, Gernert KM, Nettles JH, Aneja R (2011) Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 31(3):443–481. https://doi.org/10.1002/med.20242

    Article  CAS  PubMed  PubMed Central  Google 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):401–416

    CAS  PubMed  Google Scholar 

  38. Xu K, Schwarz PM, Ludueña RF (2002) Interaction of nocodazole with tubulin isotypes. Drug Dev Res 55(2):91–96

    Article  CAS  Google 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):183–190

    Article  CAS  Google 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):34–38

    Article  CAS  Google 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

    Article  CAS  PubMed  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):863–870

    Article  CAS  Google Scholar 

  43. Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM (2015) P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: a review. J Adv Res 6(1):45–62. https://doi.org/10.1016/j.jare.2014.11.008

    Article  CAS  PubMed  Google Scholar 

  44. Kavallaris M, Burkhart CA, Horwitz SB (1999) Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol. Br J Cancer 80(7):1020–1025. https://doi.org/10.1038/sj.bjc.6690507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stengel C, Newman SP, Leese MP, Potter BV, Reed MJ, Purohit A (2010) Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents. Br J Cancer 102(2):316–324. https://doi.org/10.1038/sj.bjc.6605489

    Article  CAS  PubMed  Google 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

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was performed within the framework of COST Action CA17104 STRATAGEM -” New diagnostic and therapeutic tools against multidrug resistant tumors”.

Funding

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).

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Authors and Affiliations

  1. Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11060, Serbia

    Jelena Dinić & Milica Pešić

  2. BioLab, Instituto Universitario de Bio-Organica “Antonio Gonzalez” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/ Astrofísico Avda. Astrofisico Francisco Sánchez 2, La Laguna, Tenerife, 38206, Spain

    Carla Ríos-Luci, Miguel X. Fernandes & José M. Padrón

  3. Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225, Vilnius, Lithuania

    Ieva Karpaviciene & Inga Cikotiene

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  1. Jelena Dinić
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Correspondence to Jelena Dinić or José M. Padrón.

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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

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