British journal of pharmacology · 2025
Anti-mitotic agent SB-216 overcomes taxane resistance in castration-resistant prostate cancer and exhibits anti-tumour efficacy in pancreatic cancer.
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Wang Rui, Cai Chun, Deng Shanshan, Xie Yang, Pochampally Satyanarayana, Hamilton David J, Meibohm Bernd, Glazer Evan S, Miller Duane D, Li Wei
Аннотация
BACKGROUND AND PURPOSE: The clinical success of small-molecule drugs in treating pancreatic and prostate cancer patients has been both promising and challenging. Whereas patients with advanced-stage tumours have significant initial responses to chemotherapy, many have experienced rapid resistance, metastasis and recurrence after curative-intent surgery. Traditional tubulin inhibitors are widely used in cancer treatment, but their effectiveness is often limited by drug resistance and toxicity. SB-216, a novel colchicine-binding site inhibitor (CBSI), has been reported to demonstrate potential efficacy in overcoming paclitaxel (PTX) resistance in a melanoma xenograft model (A375/TxR) and inhibiting spontaneous metastasis.
EXPERIMENTAL APPROACH: We evaluated SB-216 as a therapeutic option for advanced malignancies, specifically castration-resistant prostate cancer (CRPC) and pancreatic ductal adenocarcinoma (PDAC). We conducted preclinical evaluations of SB-216 in CRPC parental and taxane-resistant lines. Additionally, we investigated the effects of SB-216 on PDAC cells, xenograft models and patient-derived models.
KEY RESULTS: In vitro, SB-216 potently induces G2/M phase cell cycle arrest, inhibits cell proliferation, colony formation and cell migration in a concentration-dependent manner. In vivo, SB-216 significantly attenuates tumour growth in prostate cancer xenograft models, overcomes PTX resistance and confers a survival benefit at a dose of 2 mg kg-1 without affecting body weight. SB-216 also inhibits the growth of PDAC xenograft tumours and the growth of patient-derived cells and organoids.
CONCLUSIONS AND IMPLICATIONS: Our findings suggest that SB-216 is a promising candidate as a new generation of anti-mitotic agents for advanced cancer, and further exploration in combination with other agents is warranted.
EXPERIMENTAL APPROACH: We evaluated SB-216 as a therapeutic option for advanced malignancies, specifically castration-resistant prostate cancer (CRPC) and pancreatic ductal adenocarcinoma (PDAC). We conducted preclinical evaluations of SB-216 in CRPC parental and taxane-resistant lines. Additionally, we investigated the effects of SB-216 on PDAC cells, xenograft models and patient-derived models.
KEY RESULTS: In vitro, SB-216 potently induces G2/M phase cell cycle arrest, inhibits cell proliferation, colony formation and cell migration in a concentration-dependent manner. In vivo, SB-216 significantly attenuates tumour growth in prostate cancer xenograft models, overcomes PTX resistance and confers a survival benefit at a dose of 2 mg kg-1 without affecting body weight. SB-216 also inhibits the growth of PDAC xenograft tumours and the growth of patient-derived cells and organoids.
CONCLUSIONS AND IMPLICATIONS: Our findings suggest that SB-216 is a promising candidate as a new generation of anti-mitotic agents for advanced cancer, and further exploration in combination with other agents is warranted.