Arora Nivedita, Alsaied Osama, Dauer Patricia, Majumder Kaustav, Modi Shrey, Giri Bhuwan, Dudeja Vikas, Banerjee Sulagna, Von Hoff Daniel, Saluja Ashok
Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.
Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
PLoS One. 2017 Feb 13;12(2):e0171827. doi: 10.1371/journal.pone.0171827. eCollection 2017.
Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11.
Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice.
Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model.
Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers.
胃癌是全球癌症相关死亡的第三大主要原因，生存率较低。尽管已经使用了多种化疗药物来治疗这种疾病，但胃癌对这些药物并不特别敏感。在本研究中，我们评估了雷公藤甲素（一种天然衍生的二萜三环氧化物）及其水溶性前药米内立德对几种胃腺癌细胞系的作用，包括单药治疗以及与伊立替康（CPT - 11）联合使用的情况。
在体外，用不同剂量的雷公藤甲素处理胃癌细胞系MKN28和MKN45。使用基于MTT的检测试剂盒测量细胞活力。通过测量半胱天冬酶活性来检测细胞凋亡性死亡。通过将胃癌细胞皮下植入无胸腺裸鼠来评估雷公藤甲素前药米内立德的作用。
在体外，当用不同剂量的雷公藤甲素处理时，胃癌细胞系MKN28和MKN45细胞的活力降低，凋亡增加。当植入无胸腺裸鼠时，用米内立德治疗可减轻MKN28来源的肿瘤以及MKN45来源的肿瘤的肿瘤负担。此外，我们还在NCI - N87人胃肿瘤异种移植模型中评估了米内立德作为单一药物以及与CPT - 11联合使用的情况。
我们的结果表明，与对照组相比，米内立德与CPT - 11联合使用可使肿瘤明显缩小。由于米内立德目前正在进行胃肠道癌症的1期临床试验，这些研究非常令人鼓舞。
