Tamturk Erkut, Yalcın Serap, Ercan Fahriye, Tuncbilek Aydın Suzu
Department of Biology, Faculty of Art and Sciences, Erciyes University, 38100, Kayseri, Türkiye.
Department of Medical Pharmacology, Faculty of Medicine, Kırşehir Ahi Evran University, 40100, Kırşehir, Türkiye.
Anticancer Agents Med Chem. 2025;25(7):499-516. doi: 10.2174/0118715206340868241018075528.
Deaths from cancer are still very common all over the world and continue to be the focus of scientific research. Chemotherapy is one of the primary treatments used to prevent deaths from cancer. Side effects of chemotherapeutic drugs and resistance of cells to drugs are essential problems that limit the treatment process. Drug combination therapy is regarded as a significant application that inhibits the growth of tumors and is anticipated to provide a solution for the issues encountered. The combination therapy aims at a synergistic effect that will limit drug resistance and cytotoxic effects with appropriate drug combinations. In this context, we aim to investigate the , , and effects of single and combined doses of umbelliferone and irinotecan, known for their anticarcinogenic and curative effects, on MDA-MB-231 breast cancer cell lines and the model organism Background: Irinotecan is currently used as an anticarcinogenic drug. Anticarcinogenic effects of umbelliferone have also been detected. The , and impacts of single and combined doses use of these two agents are not yet available in the literature.
This study aims to determine the anticarcinogenic effects of single and combined use of umbelliferone and irinotecan at the molecular level. It also attempts to determine the binding energies of chemicals to cancerrelated proteins through docking and molecular dynamic studies.
The cytotoxic effects of individual and combinational doses of umbelliferone and irinotecan on the MDAMB- 231 cell line and were calculated by XTT and probit analyses. IC values for the cancer cells, LC, and LC values for were found. Gene expression analysis was performed to determine the effects of chemical agents on miR-7, miR-11, and miR-14, and their expression levels were found. The sequences of miRNAs not found in the literature were determined, and their molecular imaging was performed. In addition, the binding energies of irinotecan and umbelliferone to Bcl-2, Bad, and Akt1 proteins, which are known to have apoptotic effects, were found by the molecular docking method. Molecular dynamics studies of Bad proteins and chemicals were also performed. The drug potential of chemicals was determined by ADME/T analysis.
The cytotoxic effect on cells was calculated, and the IC value of umbelliferone was calculated as 158 μM, the IC value of irinotecan was calculated as 48,3 μM and the IC value was calculated as 20 μM. In the probit analysis performed to calculate the cytotoxic effects of drugs on , the LC value of umbelliferone was 2,5 μM, and the LC value was 13,4 μM. The LC value of irinotecan was found to be 0,1 μM, and the LC value was 0,28 μM. It was concluded that single and combined doses of chemicals in the invasion experiment significantly affected the spread of cells. As a result of expression analysis, a significant increase in HsamiR- 7 ( miRNA-7), Hsa-miR-14 ( miRNA-14), and Hsa-miR-11( miRNA-11) expression was observed in cells treated with umbelliferone irinotecan compared to the control groups.
In our study, it can be concluded that the cytotoxic effects of individual and combination doses of umbelliferone and irinotecan on MDA-MB-231 cells and larvae are significant. In addition, the effects of umbelliferone and irinotecan on the expression level of miR-7, which is a common and human miRNA, should be widely investigated. Expression analyses and docking studies of Hsa-miR-11 and Hsa-miR-14, which have been newly studied and are not in data repositories, are important for cancer research. In particular, the expression and binding energy of these miRNAs in new drug combinations and the expression level in different cancer cell lines are important for future studies. Another crucial point is that in vivo tests using different model species validate the usage of drugs at both single and mixed dosages. Other: As a result of this study, the , , and effects of single and combined doses of umbelliferone and irinotecan were determined. In future studies, it would be useful to determine the binding energies of umbelliferone and irinotecan to other cancer-related proteins and to find their interactions with different miRNAs. Additionally, studies on different model organisms are also important.
癌症死亡在全球范围内仍然非常普遍，并且仍然是科学研究的重点。化疗是用于预防癌症死亡的主要治疗方法之一。化疗药物的副作用和细胞对药物的耐药性是限制治疗过程的重要问题。联合药物治疗被认为是抑制肿瘤生长的一项重要应用，有望为所遇到的问题提供解决方案。联合治疗旨在通过适当的药物组合产生协同效应，从而限制耐药性和细胞毒性作用。在此背景下，我们旨在研究以其抗癌和治疗作用而闻名的伞形酮和伊立替康单剂量及联合剂量对MDA-MB-231乳腺癌细胞系和模式生物的 、 及 效应。背景：伊立替康目前用作抗癌药物。伞形酮的抗癌作用也已被检测到。这两种药物单剂量及联合剂量使用的 、 及 影响在文献中尚未见报道。
本研究旨在确定伞形酮和伊立替康单药及联合使用在分子水平上的抗癌作用。它还试图通过对接和分子动力学研究确定化学物质与癌症相关蛋白的结合能。
通过XTT和概率分析计算伞形酮和伊立替康单剂量及联合剂量对MDA-MB-231细胞系和 的细胞毒性作用。得出癌细胞的IC值、 的LC、LC值。进行基因表达分析以确定化学试剂对miR-7、miR-11和miR-14的影响，并得出它们的表达水平。确定文献中未发现的miRNA序列，并进行其分子成像。此外，通过分子对接方法得出伊立替康和伞形酮与已知具有凋亡作用的Bcl-2、Bad和Akt1蛋白的结合能。还对Bad蛋白和化学物质进行了分子动力学研究。通过ADME/T分析确定化学物质的药物潜力。
计算了对细胞的细胞毒性作用，伞形酮的IC值计算为158μM，伊立替康的IC值计算为48.3μM， 的IC值计算为20μM。在计算药物对 的细胞毒性作用的概率分析中，伞形酮的LC值为2.5μM， 的LC值为13.4μM。伊立替康的LC值为0.1μM， 的LC值为0.28μM。得出在侵袭实验中化学物质的单剂量和联合剂量显著影响细胞的扩散。表达分析结果显示，与对照组相比，用伞形酮 伊立替康处理的细胞中HsamiR-7（miRNA-7）、Hsa-miR-14（miRNA-14）和Hsa-miR-11（miRNA-11）表达显著增加。
在我们的研究中，可以得出结论，伞形酮和伊立替康单剂量及联合剂量对MDA-MB-231细胞和 幼虫的细胞毒性作用显著。此外，应广泛研究伞形酮和伊立替康对作为常见的 和人类miRNA的miR-7表达水平的影响。对新研究且不在数据储存库中的Hsa-miR-11和Hsa-miR-14进行表达分析和对接研究对癌症研究很重要。特别是，这些miRNA在新的联合药物中的表达和结合能以及在不同癌细胞系中的表达水平对未来研究很重要。另一个关键点是使用不同模型物种的体内试验验证单剂量和混合剂量药物的使用。其他：本研究结果确定了伞形酮和伊立替康单剂量及联合剂量的 、 及 效应。在未来研究中，确定伞形酮和伊立替康与其他癌症相关蛋白的结合能并找到它们与不同miRNA的相互作用将是有用的。此外，对不同模式生物的研究也很重要。
