Colchicine-Binding Site Agent CH-2-77 as a Potent Tubulin Inhibitor Suppressing Triple-Negative Breast Cancer.
Colchicine-Binding Site Agent CH-2-77 as a Potent Tubulin Inhibitor Suppressing Triple-Negative Breast Cancer.
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DOI：
10.1158/1535-7163.mct-21-0899
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发表时间：
2022-07-05
影响因子：
5.7
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Deng, Shanshan;Krutilina, Raisa I.;Hartman, Kelli L.;Chen, Hao;Parke, Deanna N.;Wang, Rui;Mahmud, Foyez;Ma, Dejian;Lukka, Pradeep B.;Meibohm, Bernd;Seagroves, Tiffany N.;Miller, Duane D.;Li, Wei
三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌。与其他乳腺癌亚型不同，TNBC缺乏激素和生长因子受体靶点。靶向微管蛋白的秋水仙碱结合位点抑制剂（CBSI）已被认为是有吸引力的癌症治疗药物，但目前还没有FDA批准的CBSI药物。据报道，CH-2-77在体外对一组癌细胞具有有效的抗增殖活性，并对黑素瘤异种移植物具有有效的抗肿瘤作用，但其特异性针对TNBC的抗癌活性尚不清楚。在此，我们证明CH-2-77抑制紫杉醇敏感性和紫杉醇耐药性TNBC细胞的增殖，平均IC 50为3 nM。CH-2-77还有效地破坏微管组装，抑制TNBC细胞的迁移和侵袭，并诱导G2/M细胞周期停滞。在处理的MDA-MB-231细胞中凋亡细胞数量的增加和凋亡相关蛋白的表达模式表明CH-2-77通过内在凋亡途径诱导细胞凋亡。在体内，CH-2-77显示出可接受的总体药代动力学，并且当每周给药5次时，强烈抑制原位MDA-MB-231异种移植物的生长，而没有总体累积毒性。CH-2-77（20 mg/kg）的体内功效与CA 4P（28 mg/kg）相当，CA 4P是一种经过临床试验的CBSI。重要的是，CH-2-77以剂量依赖性方式预防源自乳腺脂肪垫的肺转移。我们的数据表明，CH-2-77是一个有前途的新一代微管蛋白抑制剂，抑制TNBC的生长和转移，它是值得进一步开发的抗癌药物。
Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer. Unlike other subtypes of breast cancer, TNBC lacks hormone and growth factor receptor targets. Colchicine-binding site inhibitors (CBSIs) targeting tubulin have been recognized as attractive agents for cancer therapy, but there are no CBSI drugs currently FDA-approved. CH-2-77 has been reported to have potent anti-proliferative activity against a panel of cancer cells in vitro and efficacious anti-tumor effects on melanoma xenografts, yet, its anti-cancer activity specifically against TNBC is unknown. Herein, we demonstrate that CH-2-77 inhibits the proliferation of both paclitaxel-sensitive and paclitaxel-resistant TNBC cells with an average IC50 of 3 nM. CH-2-77 also efficiently disrupts the microtubule assembly, inhibits the migration and invasion of TNBC cells, and induces G2/M cell cycle arrest. The increased number of apoptotic cells and the pattern of expression of apoptosis-related proteins in treated MDA-MB-231 cells suggests that CH-2-77 induces cell apoptosis through the intrinsic apoptotic pathway. In vivo, CH-2-77 shows acceptable overall pharmacokinetics and strongly suppresses the growth of orthotopic MDA-MB-231 xenografts without gross cumulative toxicities when administered 5 times a week. The in vivo efficacy of CH-2-77 (20 mg/kg) is comparable to that of CA4P (28 mg/kg), a CBSI that went through clinical trials. Importantly, CH-2-77 prevents lung metastasis originating from the mammary fat pad in a dose-dependent manner. Our data demonstrate that CH-2-77 is a promising new generation of tubulin inhibitors that inhibit the growth and metastasis of TNBC, and it is worthy of further development as an anticancer agent.