PO.CH01.05 · 化学
放线菌素D与白藜芦醇联合可对消化呼吸道癌产生协同抗癌活性
The combination of actinomycin D and resveratrol induces synergistic anticancer activities against aerodigestive tract cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
联合使用多种药物以提高药理疗效或降低毒性的做法在癌症化疗中被广泛采用。放线菌素D（Act D）是首个FDA批准的抗癌抗生素。然而，其广泛应用因严重的剂量相关毒性而受阻。在本研究中，我们探讨了Act D与白藜芦醇（一种富含于红葡萄和葡萄酒中的天然膳食化合物）联合的体外和体内抗癌疗效。我们发现Act D与白藜芦醇联合可在体外协同抑制癌细胞生长。我们还通过研究p53通路的激活（包括p53靶基因p21、PUMA和GDF15的表达）探讨了这一协同疗效的潜在机制。与细胞生长抑制一致，Act D、白藜芦醇及其联合均激活p53并诱导p21、PUMA和GDF15的mRNA及蛋白表达。联合用药的效果优于任一单药。通过shRNA消除p53表达几乎完全消除了p21、PUMA和GDF15的表达，提示这些基因的表达为p53依赖性。最后，我们采用裸鼠MDA686TU（686TU）异种移植瘤模型研究了这些药物及其联合的体内疗效。尽管Act D、白藜芦醇及其联合均显著抑制异种移植瘤的生长，但与单药相比联合用药并未产生更好的效果。这些化合物的体内疗效进一步得到肿瘤组织中Ki-67表达的支持。综上所述，我们的研究结果表明，尽管Act D与白藜芦醇联合在体外显示出协同效应，但体内疗效并非如此。由P20GM103434和R15DE032063资助。
查看英文原文 English abstract
The practice of combining multiple drugs to increase pharmacological efficacy or reduce toxicity is widely adopted in cancer chemotherapeutics. Actinomycin D (Act D) is the first FDA-approved anticancer antibiotic. However, it's widespread application was hindered by severe dose-related toxicities. In the current study, we investigated the in vitro and in vivo anticancer efficacy of the combination of Act D with resveratrol, a natural dietary compound abundant in red grapes and wines. We found that the combination of Act D and resveratrol synergistically inhibited cancer cell growth in vitro . We also explored the underlying mechanism of this synergistic efficacy by investigating the activation of p53 pathway including the expression of p53 target genes p21 , PUMA and GDF15 . Consistent with the cell growth inhibition, Act D, resveratrol and their combination activated p53 and induced the expression of p21, PUMA and GDF15 mRNA and proteins. The combination had better effects than any of the single agent. Ablation of p53 expression by shRNA almost completely abolished the expression of p21, PUMA and GDF15 suggesting p53-dependent expression of these genes. Finally, we investigated the in vivo efficacy of these agents and their combination using MDA686TU (686TU) xenografts in nude mice. Although both Act D, resveratrol and their combination significantly inhibited the growth of xenografts, the combination did not have better effects when compared to single agent. The in vivo efficacy of these compounds was further supported by Ki-67 expression in tumor tissues. Taken together, our findings demonstrated that although the combination of Act D and resveratrol showed synergistic effects in vitro , the in vivo efficacy was not. Supported by P20GM103434 and R15DE032063.
利益披露 Disclosure
R. M. Lukmon, None..
J. F. Amin, None..
A. R. Amin, None.