Anti-cancer effects of CQBTO, a chloroquine, and benzo(e)triazine oxide conjugate
Anti-cancer effects of CQBTO, a chloroquine, and benzo(e)triazine oxide conjugate
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CQBTO（一种氯喹）和氧化苯并（e）三嗪结合物的抗癌作用
DOI：
10.1111/cbdd.13477
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发表时间：
2019-05-01
影响因子：
3
通讯作者：
Zhou, Guangming
中科院分区：
文献类型：
--
作者：
Guo, Ziyang;Pei, Hailong;Zhou, Guangming
目的自噬是一种自我保护的过程，它使癌细胞对放化疗具有耐药性。为了诱导癌细胞死亡，设计合成了一系列含有两个关键化学基团的3-（（4-（（7-氯喹啉-4-基）氨基）丁基）氨基）-7-取代苯并[e][1,2,4]三嗪1-氧化物或CQBTO化合物。一种化合物苯并[e][1,2,4]三嗪1-氧化物产生自由基触发自噬，另一种化合物氯喹（CQ）是自噬的抑制剂。我们假设这些化合物可以通过诱导不完全自噬来有效地杀死癌细胞。方法采用体外培养的非小细胞肺癌细胞和小鼠体内原发性肺癌细胞，检测CQBTO对癌细胞的杀伤作用和对正常组织的毒性。采用CCK8法检测细胞活力。基因组不稳定性用细胞松弛素b阻断微核测定测定。采用碘化丙啶染色和流式细胞术分析细胞周期分布。Western blotting和免疫荧光检测LC3的诱导和定位，LC3是自噬的生物标志物。结果与CQ相比，3种CQBTO对肺癌细胞均有杀伤作用，其中CQBTO-3的杀伤作用最强。CQBTO-3在A549细胞中的LD50为21 μ M，在Calu-1细胞中的LD50为21.5 μ M，均低于CQBTO-2和CQBTO-1。CQBTO-3诱导LC3病灶和LC3II/LC3I比值的增加表明CQBTO-3诱导A549细胞自噬，而未观察到明显的微核或细胞周期阻滞。对正常小鼠无明显毒性。CQBTO-3改善了小鼠的生活质量，减少了现有肿瘤的数量和大小，抑制了肿瘤的形成。结论CQBTO-3是一种潜在的治疗肺癌的化合物。
Aim Autophagy is a self-protective process, and it confers cancer cells resistance against radio-chemotherapeutics. To induce cancer cell death, a series of compounds of 3-((4-((7-chloroquinolin-4-yl)amino)butyl)amino)-7-substituted benzo[e][1,2,4]triazine 1-oxide or CQBTO containing two critical chemical groups were designed and synthesized. One compound, benzo[e][1,2,4]triazine 1-oxide, yielded free radicals to trigger autophagy, and the other one, chloroquine (CQ), was an inhibitor of autophagy. We hypothesized that the compounds could kill cancer cells effectively by inducing incomplete autophagy. Methods In vitro cultured non-small cell lung carcinoma cells and primary lung tumors in mice in vivo were used to test the lethal effects of CQBTO on cancer cells and toxicity to normal tissues. Cell viability was examined using the CCK8 assay. Genomic instability was determined with the cytochalasin B-blocked micronucleus assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Western blotting and immunofluorescence were used to detect the induction and localization of LC3, a biomarker for autophagy. Results Compared with CQ, three CQBTO compounds were lethal to lung cancer cells, and CQBTO-3 was the most effective. The LD50 for CQBTO-3 was 21 mu M in A549 cells and 21.5 mu M in Calu-1 cells, which was lower than that of CQBTO-2 or CQBTO-1. Induction of LC3 foci and an increase in the LC3II/LC3I ratio demonstrated the induction of autophagy by CQBTO-3 in A549 cells, whereas no obvious micronuclei or cell cycle arrest was observed. No detectable toxicity to normal mice was observed. CQBTO-3 improved the quality of mouse life, reduced the number and size of existing tumors, and suppressed tumor formation. Conclusion CQBTO-3 is a potential chemical compound for lung cancer treatment.