Department of Pharmacology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901, USA.
Molecules. 2022 Jul 1;27(13):4244. doi: 10.3390/molecules27134244.
Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (-)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (-)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.
微管稳定剂（MSAs）是一类用于治疗三阴性乳腺癌（TNBC）的化合物，TNBC 是乳腺癌的一种亚型，化疗仍然是患者的标准治疗方法。紫杉醇和多西他赛等紫杉烷类药物已在临床上显示出对 TNBC 的疗效，但由于患者对紫杉烷类药物的耐药性上升，需要确定新的 MSA 类别。(-)-Zampanolide 是一种共价微管稳定剂，可在体外规避紫杉烷类药物的耐药性，但尚未对其体内抗肿瘤疗效进行评估。在这里，我们确定(-)-zampanolide 在 TNBC 细胞系中的效力和疗效与紫杉醇相似，但由于其共价结合，它的持久性显著更高。我们还提供了(-)-zampanolide 的首次体内抗肿瘤评估，其中我们确定它在肿瘤内给药时具有强大且持久的抗肿瘤疗效。未来对 zampanolide 的研究将进一步评估其药效团，并确定改善其系统治疗窗口的方法，这将使该化合物通过规避紫杉烷耐药机制成为临床开发的潜在候选药物。
