Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma. (1st February 2022)

• Record Type: Journal Article
• Authors: Bell, Clayton J.; Potts, Kyle G.; Hitt, Mary M.; Pink, Desmond; Tuszynski, Jack A.; Lewis, John D.
• Is Part Of: Cancer letters. Volume 526(2022)
• Page Start: 168
• Page End: 179
• Publication Date: 2022-02-01
• Subjects: Anti-mitotic drug -- βIII tubulin -- rational drug design -- tubulin polymerization inhibitor -- structural analogues; IC50 50% inhibitory concentration -- PDX patient derived xenograft; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.11.028
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: ∙ CR42-24 blocks microtubule dynamics, induces metaphase arrest in cancer cells. ∙CR42-24 is highly effective against many cancers, and especially urothelial carcinoma. ∙CR42-24 reduces cancer cell viability with better tolerability vs combination therapy