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

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

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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