Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma
| Autor: | Mary M. Hitt, Clayton Bell, Kyle G. Potts, Desmond Pink, Jack A. Tuszynski, John D. Lewis |
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| Rok vydání: | 2022 |
| Předmět: |
Male
Cancer Research Mice SCID Mice chemistry.chemical_compound Mice Inbred NOD In vivo Cell Line Tumor Animals Humans Colchicine Medicine Cytotoxic T cell Cisplatin Carcinoma Transitional Cell biology business.industry Xenograft Model Antitumor Assays Tubulin Modulators Gemcitabine In vitro Disease Models Animal Tubulin Urinary Bladder Neoplasms Oncology Tolerability chemistry biology.protein Cancer research business HeLa Cells medicine.drug |
| Zdroj: | Cancer Letters. 526:168-179 |
| ISSN: | 0304-3835 |
| Popis: | Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the βIII tubulin subtype as a treatment for urothelial carcinoma. βIII tubulin is a promising target due to its low expression in healthy tissues and its clinical association with poor prognosis. This study demonstrated that CR42-24 is selectively cytotoxic to several cancer cell lines at low nanomolar IC50, with high activity in bladder cancer cell lines both in vitro and in vivo. CR42-24 monotherapy in an aggressive urothelial carcinoma xenograft model results in effective control when treated early. We observed significant ablation of large tumors and patient-derived xenografts at low doses with excellent tolerability. CR42-24 was highly synergistic in combination with the standard of care chemotherapies gemcitabine and cisplatin, further increasing its therapeutic potential as a novel treatment for urothelial carcinoma. |
| Databáze: | OpenAIRE |
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