Ruthenocenyl and 1-Adamantyl Paclitaxel Analogs Disrupt the Balance between βIII- and βIVa-Tubulin and Inhibit the Growth and Invasiveness of Colon Cancer

  • J Med Chem. 2025 Sep 25;68(18):19062-19075. doi: 10.1021/acs.jmedchem.5c01147.
Wojciech M Ciszewski  1 ,  Karolina Kowalczyk  2 ,  Andrzej Błauż  3 ,  Wojciech Ciesielski  4 ,  Piotr Hogendorf  4 ,  Beata Smolarz  5 ,  Waldemar Wagner  6 ,  Anna Wieczorek-Błauż  7 ,  Błażej Michał Rychlik  3 ,  Hanna Romanowicz  5 ,  Adam Durczyński  4 ,  Katarzyna Sobierajska  1 ,  Damian Plażuk  2
Affiliations
  • 1. Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland.
  • 2. Laboratory of Molecular Spectroscopy, Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, Lodz 91-403, Poland.
  • 3. Centre for Digital Biology and Biomedical Science - Biobank Lodz, Faculty of Biology and Environmental Protection, University of Lodz, ul. Pomorska 141/143, Łódź 90-236, Poland.
  • 4. Department of General and Transplant Surgery, Medical University of Lodz, Kopcinskiego 22, Lodz 90-419, Poland.
  • 5. Laboratory of Cancer Genetics, Department of Pathology, Polish Mother's Memorial Hospital Research Institute, Rzgowska 281/289, Lodz 93-338, Poland.
  • 6. Laboratory of Cellular Immunology, Institute of Medical Biology PAS, Lodowa 106, Lodz 93-232, Poland.
  • 7. Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, Lodz 91-403, Poland.
PMID: 40907950 DOI: 10.1021/acs.jmedchem.5c01147
Abstract

Taxanes are widely used Anticancer agents that stabilize microtubules and arrest cell division. However, their efficacy in colon Cancer is limited by the chemoresistance associated with βIII-tubulin (TUBB3) upregulation. Herein, ferrocenyl, ruthenocenyl, and 1-adamantyl analogs of paclitaxel were synthesized and biologically evaluated. All compounds exhibited significantly higher cytotoxicity than paclitaxel, with IC50 values in the nanomolar range. Ruthenocenyl and 1-adamantyl analogs effectively inhibited both growth and invasiveness of colon Cancer cells. These effects correlated with altered tubulin isoform expression (downregulation of βIII-tubulin and upregulation of βIVa-tubulin) were associated with modulation of the focal adhesion complex. Specifically, changes in microtubule interactions with the integrin-linked kinase-integrin-β1 axis contributed to a reduced invasive potential. The unique properties of these analogs suggest their potential for dual-action therapy combining tumor growth inhibition with metastasis prevention.

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