Benzimidazole carbamate induces cytotoxicity in breast cancer cells via two distinct cell death mechanisms.
Benzimidazole carbamate induces cytotoxicity in breast cancer cells via two distinct cell death mechanisms.
复制标题
DOI：
10.1038/s41420-023-01454-6
复制
发表时间：
2023-05-13
影响因子：
7
通讯作者：
Yan, Ying
中科院分区：
文献类型：
--
作者：
Graff, Brendan T.;Palanivel, Chitra;Jenkins, Christopher B.;Baranowska-Kortylewicz, Janina;Yan, Ying
转移性乳腺癌（mBC）导致>90%的乳腺癌相关死亡。微管靶向剂（MTA）是mBC的一线治疗。然而，MTA的有效性经常受到原发性或获得性耐药性的限制。此外，衍生自MTA治疗后存活的癌细胞的复发性mBC通常更具化学抗性。二线和三线MTA在既往接受过MTA治疗的mBC患者中的总体缓解率为12- 35%。因此，目前正在寻找具有独特作用模式的新型MTA，其可以规避化学抗性机制。我们的研究结果表明，甲基N-（6-苯甲酰基-1H-苯并咪唑-2-基）氨基甲酸酯（BCar），微管破坏驱虫剂，结合秋水仙碱结合位点分开的临床使用的MTA的结合位点，有可能治疗MTA耐药的MBC。我们全面评估了BCar在一组人乳腺癌（BC）细胞系和正常乳腺细胞中的细胞效应。测定了BCar对克隆形成存活、细胞周期、凋亡、自噬、衰老和有丝分裂灾难的影响。大约25%的BC携带突变型p53。因此，将p53状态作为变量纳入。结果显示，BC细胞对BCar的敏感性比正常乳腺上皮细胞（HME）高> 10倍。p53突变型BC细胞对BCar处理比p53野生型BC细胞显著更敏感。此外，BCar似乎主要通过p53依赖性凋亡或p53非依赖性有丝分裂灾难来杀死BC细胞。与多西他赛和长春新碱（两种临床MTA）相比，BCar在HME细胞中相当无害，提供了比多西他赛和长春新碱更宽的治疗窗。总之，这些结果强烈支持了基于BCar的疗法可以作为mBC治疗的新的MTA系列的观点。
Metastatic breast cancer (mBC) is responsible for >90% of breast cancer-related deaths. Microtubule-targeting agents (MTAs) are the front-line treatment for mBC. However, the effectiveness of MTAs is frequently limited by the primary or acquired resistance. Furthermore, recurrent mBC derived from cancer cells that survived MTA treatment are typically more chemoresistant. The overall response rates for the second- and third-line MTAs in mBC patients previously treated with MTAs are 12–35%. Thus, there is an ongoing search for novel MTAs with a distinct mode of action that can circumvent chemoresistance mechanisms. Our results show that methyl N-(6-benzoyl-1H-benzimidazol-2-yl)carbamate (BCar), a microtubule-disrupting anthelmintic that binds to the colchicine binding site separate from the binding sites of clinically used MTAs, has the potential to treat MTA-resistant mBC. We have comprehensively evaluated the cellular effects of BCar in a panel of human breast cancer (BC) cell lines and normal breast cells. BCar effects on the clonogenic survival, cell cycle, apoptosis, autophagy, senescence, and mitotic catastrophe were measured. Approximately 25% of BCs harbor mutant p53. For this reason, the p53 status was included as a variable. The results show that BC cells are >10x more sensitive to BCar than normal mammary epithelial cells (HME). p53-mutant BC cells are significantly more sensitive to BCar treatment than p53 wild-type BC cells. Furthermore, BCar appears to kill BC cells primarily via either p53-dependent apoptosis or p53-independent mitotic catastrophe. When compared to docetaxel and vincristine, two clinical MTAs, BCar is fairly innocuous in HME cells, providing a much wider therapeutic window than docetaxel and vincristine. Together, the results strongly support the notion that BCar-based therapeutics may serve as a new line of MTAs for mBC treatment.
登录
查看更多内容
影响因子：
3.8
作者：
Lehmann BD;Ding Y;Viox DJ;Jiang M;Zheng Y;Liao W;Chen X;Xiang W;Yi Y
通讯作者：
Yi Y
影响因子：
3.9
作者：
Maeda, Shigeto;Saimura, Michiyo;Tamura, Kazuo
通讯作者：
Tamura, Kazuo
影响因子：
5.5
作者：
Khattab M;Al-Karmalawy AA
通讯作者：
Al-Karmalawy AA
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
8
作者：
Hernandez-Vargas, H.;Palacios, J.;Moreno-Bueno, G.
通讯作者：
Moreno-Bueno, G.