Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 South Daxuecheng Road, Chongqing 401331, PR China.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 South Daxuecheng Road, Chongqing 401331, PR China.
Life Sci. 2019 Feb 15;219:20-30. doi: 10.1016/j.lfs.2018.12.052. Epub 2018 Dec 31.
CAA45 is a calothrixin A (CAA) analogue with anti-cancer activity at nanomolar concentration. This study aimed to investigate the anti-lung cancer activity of CAA45 and explore its mechanisms of actions.
CAA and CAA45 were synthesized and their inhibition on DNA topoisomerase I (Topo I) performed by evaluating the relaxation of supercoiled pBR322 plasmid DNA and their anti-lung cancer capacity determined by cytotoxic assays, cell migration, cell cycle, cell apoptosis, cell autophagy and related signaling proteins expression by western blot.
CAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC values of 110 and 230 nM, respectively. In the A549 xenograft models, CAA45 displayed strong antitumor activities at a dose of 10 mg/kg. CAA45 inhibited Topo I activity and caused the cell cycle arrest at S phase, which also reduced A549 cell migration by inhibiting MMP-2 and MMP-9 expressions. Furthermore, CAA45 induced A549 cell apoptosis and autophagy. The apoptosis pathway was involved in the release of cytochrome c and caspase activation. CAA45 also inhibited Akt, activated JNK and up-regulated p53 signals in A549 cells, which may serve as a modulator to induce apoptosis and autophagy in cancer cells.
CAA45 exerted its anti-lung cancer effect via inhibition of Topo I, resulting in cell cycle arrest and cell migration, induction of mitochondria mediated cell apoptosis and autophagy via PI3K/Akt/JNK/p53 pathway. All these observations suggested that CAA45 could be a promising lead for anti-cancer drug discovery.
CAA45 是一种贝壳杉烯 A（CAA）类似物，具有纳摩尔浓度的抗癌活性。本研究旨在探讨 CAA45 的抗肺癌活性，并探讨其作用机制。
合成 CAA 和 CAA45，通过评估超螺旋 pBR322 质粒 DNA 的松弛来评价它们对 DNA 拓扑异构酶 I（Topo I）的抑制作用，并通过细胞毒性测定、细胞迁移、细胞周期、细胞凋亡、细胞自噬和相关信号蛋白表达的 Western blot 来确定它们的抗肺癌能力。
CAA45 显著抑制人非小细胞肺癌 A549 和 NCI-H1650 细胞生长，IC 值分别为 110 和 230 nM。在 A549 异种移植模型中，CAA45 在 10mg/kg 剂量下表现出很强的抗肿瘤活性。CAA45 抑制 Topo I 活性并导致细胞周期停滞在 S 期，这也通过抑制 MMP-2 和 MMP-9 的表达来减少 A549 细胞迁移。此外，CAA45 诱导 A549 细胞凋亡和自噬。凋亡途径涉及细胞色素 c 的释放和半胱天冬酶的激活。CAA45 还抑制 A549 细胞中的 Akt，激活 JNK 并上调 p53 信号，这可能作为一种调节剂，诱导癌细胞凋亡和自噬。
CAA45 通过抑制 Topo I 发挥其抗肺癌作用，导致细胞周期停滞和细胞迁移，通过 PI3K/Akt/JNK/p53 通路诱导线粒体介导的细胞凋亡和自噬。所有这些观察结果表明，CAA45 可能是一种有前途的抗癌药物发现的先导化合物。
