Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Mar Drugs. 2018 Nov 30;16(12):479. doi: 10.3390/md16120479.
11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral , has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was applied to evaluate cell cycle distribution and apoptosis. The expression of proteins related to the cell cycle and apoptosis was analyzed by Western blot analysis. Additionally, an in vivo study was performed to determine the anti-SCLC effect on an H1688 subcutaneous tumor in a BALB/c nude mouse model. 11-Dehydrosinulariolide inhibited cell growth, triggered G2/M arrest and induced H1688 cell apoptosis in a dose- and time-dependent manner. Additionally, 11-dehydrosinulariolide caused the accumulation of p53 and Bax, accompanied by the activation of DNA damage-inducing kinases, including ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2). Moreover, 11-dehydrosinulariolide increased the activity of caspase-3 and -7, suggesting that caspases are involved in 11-dehydrosinulariolide-induced apoptosis. 11-Dehydrosinulariolide also increased the level of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibited the expression of phosphorylated Akt. In the in vivo study, the intraperitoneal injection of 11-dehydrosinulariolide at a dosage of 10 mg/kg significantly inhibited tumor growth compared with the control treatment. Together, the data indicate that 11-dehydrosinulariolide induces G (2)/M cell cycle arrest and apoptosis through various cellular processes, including the upregulation of p53 and Bax, activation of ATM and Chk2, activation of caspase-3 and -7, and accumulation of PTEN, leading to inhibition of the Akt pathway. These findings suggest that 11-dehydrosinulariolide might serve as a promising chemotherapy drug in the treatment of SCLC.
11-脱水海兔内酯是一种从培养的软珊瑚中分离出来的活性化合物，根据先前的研究表明，它具有抗肿瘤的生物学特性。然而，其对小细胞肺癌（SCLC）的潜在作用尚不清楚。本研究旨在体外和体内研究其治疗 SCLC 的潜在机制。通过甲基噻唑二苯基四氮唑（MTT）法检测细胞活力。采用流式细胞术评估细胞周期分布和细胞凋亡。通过 Western blot 分析检测与细胞周期和细胞凋亡相关的蛋白表达。此外，还进行了一项体内研究，以确定 11-脱水海兔内酯对 BALB/c 裸鼠 H1688 皮下肿瘤的抗 SCLC 作用。11-脱水海兔内酯呈剂量和时间依赖性地抑制细胞生长，引发 G2/M 期阻滞并诱导 H1688 细胞凋亡。此外，11-脱水海兔内酯导致 p53 和 Bax 的积累，同时激活包括共济失调毛细血管扩张突变（ATM）和检查点激酶 2（CHK2）在内的 DNA 损伤诱导激酶。此外，11-脱水海兔内酯增加了 caspase-3 和 caspase-7 的活性，提示 caspase 参与了 11-脱水海兔内酯诱导的细胞凋亡。11-脱水海兔内酯还增加了肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）的水平，并抑制了磷酸化 Akt 的表达。在体内研究中，与对照组相比，腹腔注射 11-脱水海兔内酯（剂量为 10mg/kg）显著抑制了肿瘤生长。综上所述，数据表明 11-脱水海兔内酯通过多种细胞过程诱导 G（2）/M 细胞周期阻滞和细胞凋亡，包括上调 p53 和 Bax，激活 ATM 和 Chk2，激活 caspase-3 和 caspase-7，以及积累 PTEN，从而抑制 Akt 通路。这些发现表明 11-脱水海兔内酯可能成为治疗 SCLC 的一种有前途的化疗药物。
