Mechanisms of cytotoxic activity of pyrrole-carboxamides against multidrug-resistant tumor cell sublines

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Abstract

Introduction. Mitotic poisoning agents (MPAs) affecting the dynamic state of the microtubules, are the well-known and effective chemotherapeutic agents. Mitotic poisoning agents are binding to the microtubules, and thereby interfere with tubulin polymerization or depolymerization dynamic state, resulting in the cell cycle arrest in M-phase (mitotic catastrophe) and subsequent apoptotic cell death. We reported previously about potent cytotoxic activities against the pyrrole-carboxamides (PCs) (PC-61 and PC-84) against broad spectrum of cancer cell lines, including triple negative breast cancer, lung and prostate cancer.

Aim. To examine the cytotoxic activities of PC-61 and PC-84 against multidrug-resistant cancer cell lines indicated above.

Materials and methods. Studу was performed on the triple-negative paclitaxel-resistant breast cancer cell line HCC1806 Tx-R and doxorubicin-resistant osteosarcoma SaOS-2 Dox-R cell line.

Results. The cytotoxic activity of PCs was due to the inhibition of tubulin polymerization. Immunofluorescence staining data revealed PC’s ability to interfere with tubulin’s assembly in multidrug-resistant cancer cell lines. As an outcome of inhibition of tubulin polymerization, PCs induced cell cycle arrest in M-phase, and further led to apoptotic cell death of cancer cells.

Conclusion. Collectively, we demonstrated potent cytotoxic activity of PCs against cancer cell lines with multidrug-resistant phenotype, which arising the possibilities to develop novel and effective anti-tumor agents that belongs to mitotic poisoning agents

About the authors

A. R. Galembikova

Kazan State Medical University, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0002-0293-2974

49 Butlerova St., Kazan 420012

Russian Federation

P. D. Dunaev

Kazan State Medical University, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0002-5449-4435

49 Butlerova St., Kazan 420012

Russian Federation

F. F. Bikinieva

Kazan State Medical University, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0002-9012-6525

49 Butlerova St., Kazan 420012

Russian Federation

I. G. Mustafin

Kazan State Medical University, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0001-9683-3012

49 Butlerova St., Kazan 420012

Russian Federation

P. B. Kopnin

Research Institute of Carcinogenesis of the N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0002-2078-4274

24 Kashirskoye Shosse, Moscow 115522

Russian Federation

S. S. Zykova

Perm State Pharmaceutical Academy, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0000-0002-7395-4951

2 Polevaya St., Perm 614990

Russian Federation

F. I. Mukhutdinova

Kazan State Medical University, Ministry of Health of Russia

Email: fake@neicon.ru
ORCID iD: 0009-0004-9666-0130

49 Butlerova St., Kazan 420012

Russian Federation

E. A. Sarbazyan

Kazan National Research Technological University

Email: fake@neicon.ru
ORCID iD: 0009-0005-4068-662X

68 Karl Marx St., Kazan 420015

Russian Federation

S. V. Boichuk

Kazan State Medical University, Ministry of Health of Russia; Research Laboratory “Biomarker”, Institute of Fundamental Medicine and Biology of the Kazan Federal University; Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia; Central Research Laboratory of the Kazan State Medical University, Ministry of Health of Russia

Author for correspondence.
Email: boichuksergei@mail.ru
ORCID iD: 0000-0003-2415-1084

18 Kremlevskaya St., Kazan 420008
Bld. 1, 2 / 1 Barricadnaya St., Moscow 125993
49 Butlerova St., Kazan 420012
49 Butlerova St., Kazan 420012

Russian Federation

References

  1. Parker A.L., Kavallaris M., McCarroll J.A. Microtubules and their role in cellular stress in cancer. Front Oncol 2014;4:1–19. doi: 10.3389/fonc.2014.00153
  2. Dumontet C., Jordan M.A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 2010;9(10): 790–803. doi: 10.1038/nrd3253
  3. Gigant B., Wang C., Ravelli R.B. et al. Structural basis for the regulation of tubulin by vinblastine. Nature 2005;435(7041):519–22. doi: 10.1038/nature03566
  4. Ravelli R.B., Gigant G., Curmi B. et al. Insight into tubulin regulation from a complex with colchicine and a stathminlike domain. Nature 2004;428(6979):198–202. doi: 10.1038/nature02393
  5. Yang J., Wang Y., Wang T. et al. Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule. Nat Commun 2016;7:12103. doi: 10.1038/ncomms12103
  6. Prota A.E., Setter J., Waight A.B. et al. Pironetin binds covalently to αCys316 and perturbs a major loop and helix of α-tubulin to inhibit microtubule formation. J Mol Biol 2016;428(15):2981–8. doi: 10.1016/j.jmb.2016.06.023
  7. Steinmetz M.O., Prota A.E. Microtubule-targeting agents: strategies to hijack the cytoskeleton. Trends Cell Biol 2018;28(10):776–92. doi: 10.1016/j.tcb.2018.05.001
  8. Fanale D., Bronte G., Passiglia F. et al. Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option? Anal Cell Pathol 2015;2015:690916. doi: 10.1155/2015/690916
  9. Mooberry S.L., Tien G., Hernandez A.H. et al. Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. Cancer Res 1999;59(3):653–60.
  10. West L.M., Northcote P.T., Battershill C.N., Peloruside A. A potent cytotoxic macrolide isolated from the New Zealand marine sponge Mycale sp. J Org Chem 2000;65(2):445–9. doi: 10.1021/jo991296y
  11. Prota A.E., Bargsten K., Northcote P.T. et al. Structural basis of microtubule stabilization by laulimalide and peloruside A. Angew Chem Int Ed Engl 2014;53(6):1621–5. doi: 10.1002/anie.201307749
  12. Munshi N., Jeay S., Li Y. et al. ARQ 197, a novel and selective inhibitor of the human c-met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther 2010;9(6):1544–53. doi: 10.1158/1535-7163.MCT-09-1173
  13. Katayama R., Aoyama A., Yamori T. et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res 2013;73(10):3087–96. doi: 10.1158/0008-5472.CAN-12-3256
  14. Aoyama A., Katayama R., Oh-Hara T. et al. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance. Mol Cancer Ther 2014;13(12):2978–90. doi: 10.1158/1535-7163.MCT-14-0462
  15. Gumireddy K., Reddy M.V.R., Cosenza S.C. et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 2005;7:275–86. doi: 10.1016/j.ccr.2005.02.009
  16. Jost M., Chen Y., Gilbert L.A. et al. Combined CRISPRi/a-based chemical genetic screens reveal that rigosertib is a microtubuledestabilizing agent. Mol Cell 2017;68(1):210–23. doi: 10.1016/j.molcel.2017.09.012
  17. Park H., Hong S., Hong S. Nocodazole is a high-affinity ligand for the cancer-related kinases ABL, c-KIT, BRAF, and MEK. Chem Med Chem 2012;7(1):53–6. doi: 10.1002/cmdc.201100410
  18. Guo X., Zhang X., Li Y. et al. Nocodazole increases the ERK activity to enhance MKP-1 expression which inhibits p38 activation induced by TNF-α. Mol Cell Biochem 2012;364(1–2):373–80. doi: 10.1007/s11010-012-1239-5
  19. Tanabe K. Microtubule depolymerization by kinase inhibitors: unexpected findings of dual inhibitors. Int J Mol Sci 2017;18(12):2508. doi: 10.3390/ijms18122508
  20. Ramirez-Rios S., Michallet S., Peris L. et al. A new quantitative cell-based assay reveals unexpected microtubule stabilizing activity of certain kinase inhibitors, clinically approved or in the process of approval. Front Pharmacol 2020;11:543. doi: 10.3389/fphar.2020.00543
  21. Krishna R., Mayer L.D. Multidrug resistance (MDR) in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000;11(4):265–83. doi: 10.1016/S0928-0987(00)00114-7
  22. Mechetner E., Kyshtoobayeva A., Zonis S. et al. Levels of multidrug resistance (MDR1) P-glycoprotein expressing by human breast cancer correlate with in vitro resistance to taxol and doxorubicin. Clin Cancer Res 1998;4(2):389–98.
  23. Kavallaris M., Kuo D.Y., Burkhart C.A. et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Investig 1997;100(5):1282– 93. doi: 10.1172/JCI119642
  24. Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 2010;10(3):194–204. doi: 10.1038/nrc2803
  25. Zykova S.S., Boychuk S.V., Galimbekova A.R. et al. 3-hydroxy-1,5diaryl-4-pivaloyl-2,5-dihydro-2-pyrrolone disrupt mitosis processes and induce the death of tumor cells in vitro. Citologiya = Cytology 2014;56:439–42. (In Russ.).
  26. Boichuk S., Galembikova A., Zykova S. et al. Ethyl-2-aminopyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue cancer cell growth in vitro. Anti-Cancer Drugs 2016;27(7):620–34. doi: 10.1097/CAD.0000000000000372
  27. Boichuk S., Galembikova A., Dunaev P. et al. Ethyl-2-aminopyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo. Anti-Cancer Drugs 2019;30(5):475–84. doi: 10.1097/CAD.0000000000000753
  28. Carta D., Bortolozzi R., Sturlese M. et al. Synthesis, structureactivity relationships and biological evaluation of 7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic agents. Eur J Med Chem 2017;127:643–60. doi: 10.1016/j.ejmech.2016.10.026
  29. Brindisi M., Ulivieri C., Alfano G. et al. Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents. Eur J Med Chem 2019;162:290–320. doi: 10.1016/j.ejmech.2018.11.004
  30. Boichuk S., Galembikova A., Syuzov K. et al. The design, synthesis, and biological activities of pyrrole-based carboxamides: the novel tubulin inhibitors targeting the colchicine-binding site. Molecules 2021;26(19):5780. doi: 10.3390/molecules26195780
  31. Boichuk S., Galembikova A., Sitenkov A. et al. Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance. Oncol Lett 2017;14(4):5039–45. doi: 10.3892/ol.2017.6795
  32. Zykova S., Kizimova I., Syutkina A. et al. Synthesis and cytostatic activity of (E)-ethyl-2-amino-5-(3,3-dimethyl-4-oxobutyliden-4oxo-1-(2-phenylaminobenzamido)-4,5-dihydro-1Hpyrrol-3carboxylate. Pharm Chem J 2020;53:895–8. doi: 10.1007/s11094020-02096-z
  33. Boichuk S., Bikinieva F., Valeeva E. et al. Establishment and characterization of multi-drug resistant p53-negative osteosarcoma SaOS-2 subline. Diagnostics 2023;13:2646. doi: 10.3390/diagnostics13162646
  34. Boichuk S., Dunaev P., Mustafin I. et al. Infigratinib (BGJ 398), a pan-FGFR inhibitor, targets P-glycoprotein and increases chemotherapeutic-induced mortality of multidrug-resistant tumor cells. Biomedicines 2022;10(3):601. doi: 10.3390/biomedicines10030601
  35. Distefano M., Scambia G., Ferlini C. et al. Antitumor activity of paclitaxel (taxol) analogues on MDR-positive human cancer cells. Anticancer Drug Des 1998;13(5):489–99.
  36. Pirol Ş.C., Çalışkan B., Durmaz I. et al. Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3carboxylic acid amides with potent anti-proliferative activity on human cancer cell lines. Eur J Med Chem 2014;87:140–9. doi: 10.1016/j.ejmech.2014.09.056
  37. Ke J., Lu Q., Wang X. et al. Discovery of 4,5-dihydro-1Hthieno[2’,3’:2,3]thiepino [4,5-c]pyrazole-3-carboxamide derivatives as the potential epidermal growth factor receptors for tyrosine kinase inhibitors. Molecules 2018;23:1980. doi: 10.3390/molecules23081980
  38. Lin T., Li J., Liu L. et al. Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors. Eur J Med Chem 2021;215:113281. doi: 10.1016/j.ejmech.2021.113281
  39. Yasuda Y., Arakawa T., Nawata Y. et al. Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors. Bioorg Med Chem 2015;23(8):1776–87. doi: 10.1016/j.bmc.2015.02.038
  40. Gul H.I., Mete E., Eren S.E. et al. Designing, synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydropyrazol-1-yl]benzenesulfonamides. J Enzyme Inhib Med Chem 2017;32(1):169–75. doi: 10.1080/14756366.2016.1243536
  41. Gul H.I., Yamali C., Bulbuller M. et al. Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes. Bioorg Chem 2018;78: 290–7. doi: 10.1016/j.bioorg.2018.03.027
  42. Gul H.I., Yamali C., Sakagami H. et al. New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors. Bioorg Chem 2018;77:411–9. doi: 10.1016/j.bioorg.2018.01.021
  43. Yamali C., Sakagami H., Uesawa Y. et al. Comprehensive study on potent and selective carbonic anhydrase inhibitors: synthesis, bioactivities and molecular modelling studies of 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1Hpyrazole-1-yl) benzenesulfonamides. Eur J Med Chem 2021;217:113351. doi: 10.1016/j.ejmech.2021.113351
  44. Mooberry S.L., Weiderhold K.N., Dakshanamurthy S. et al. Identification and characterization of a new tubulin-binding tetrasubstituted brominated pyrrole. Mol Pharmacol 2007;72(1):132–40. doi: 10.1124/mol.107.034876
  45. Da C., Telang N., Barelli P. et al. Pyrrole-based antitubulin agents: two distinct binding modalities are predicted for C-2 analogues in the colchicine site. ACS Med Chem Lett 2012;3(1):53–7. doi: 10.1021/ml200217u
  46. Romagnoli R., Oliva P., Salvador M.K. et al. A facile synthesis of diary l pyrroles led to the discovery of potent colchicine site antimitotic agents. Eur J Med Chem 2021;214:113229. doi: 10.1016/j.ejmech.2021.113229

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