Novel Benzo[a]quinolizidine Analogs Induce Cancer Cell Death through Paraptosis and Apoptosis
Novel Benzo[a]quinolizidine Analogs Induce Cancer Cell Death through Paraptosis and Apoptosis
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新型苯并[a]喹啉西啶类似物通过凋亡和细胞凋亡诱导癌细胞死亡
DOI：
10.1021/acs.jmedchem.6b00484
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发表时间：
2016-05-26
影响因子：
7.3
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Zheng, Hongbo;Dong, Yiwen;Lou, Hongxiang
细胞旁凋亡是一种以大量内质网（ER）或线粒体衍生的空泡为特征的非凋亡细胞死亡。与依赖细胞凋亡的抗癌药物相比，诱导细胞凋亡在治疗化疗耐药肿瘤方面具有显著优势。由于一些天然生物碱可诱导细胞旁凋亡死亡，合成了一系列新的苯并[a]喹诺齐啶衍生物，并分析了它们的抗增殖活性和诱导细胞质空泡化的能力。通过结构优化，鉴定出了有效的化合物22b，该化合物在体外和体内均能抑制癌细胞增殖，并能深刻促进细胞凋亡样死亡和诱导caspase依赖性凋亡。进一步研究表明，22b介导的空泡形成源于持续内质网应激和LC3B的上调。因此，苯并[a]喹诺齐啶衍生物引起的细胞凋亡代表了癌症化疗的另一种策略。
Paraptosis is nonapoptotic cell death characterized by massive endoplasmic reticulum (ER)- or mitochondria-derived vacuoles. Induction of paraptosis offers significant advantages for the treatment of chemotherapy-resistant tumors compared with anticancer drugs that rely on apoptosis. Because some natural alkaloids induce paraptotic cell death, a novel series of benzo[a]quinolizidine derivatives were synthesized, and their antiproliferative activity and ability to induce cytoplasmic vacuolation were analyzed. Structural optimization led to the identification of the potent compound 22b, which inhibited cancer cell proliferation in vitro and in vivo and profoundly facilitated paraptosis-like cell death and induced caspase-dependent apoptosis. Further investigation revealed that 22b-mediated vacuolation originated from persistent ER stress and upregulation of LC3B. Paraptosis induced by benzo[a]quinolizidine derivatives thus represents an alternative strategy for cancer chemotherapy.