Abstract：
BACKGROUND: Melanoma is a highly aggressive neoplasm with a high degree of malignancy and rapid acquisition of resistance by cancer cells.
METHODS: Biological studies of a series of isoxazole compounds with immunomodulatory properties were preceded by in silico analysis. The assay evaluated the viability of NHDF and A375 cell cultures after the administration of isoxazole compounds after a 24-hour incubation period in the MTT test. Analyzes of ROS and NO scavenging, P-glycoprotein activity, and properties were performed. The levels of Caspase 3 and Caspase 9 were measured using ELISA to assess which pathways induced apoptosis by the tested compounds. On the chip, the synergistic effect of doxorubicin and the most active compound from the MM9 series on cells of the A375 melanoma line was determined.
RESULTS: All tested N\'-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with immunomodulatory activity show multidirectional antitumor activity on A375 melanoma lines with an affinity for P-glycoprotein, induction of free radical formation and generation of DNA damage leading to the death of cancer cells, as well as formation of complexes with DNA Topoisomerase II. Most of the tested compounds show pro-apoptotic activity. The most active compound in the series induces apoptosis in three distinct pathways and acts synergistically with doxorubicin.
CONCLUSIONS: The most active compound with immunomodulatory properties showed multidirectional antitumor activity against cells of the A375 melanoma line and also had a synergistic pro-apoptotic effect with doxorubicin, which may result in a reduction of this cytostatic dose with increased effectiveness.
METHODS: Biological studies of a series of isoxazole compounds with immunomodulatory properties were preceded by in silico analysis. The assay evaluated the viability of NHDF and A375 cell cultures after the administration of isoxazole compounds after a 24-hour incubation period in the MTT test. Analyzes of ROS and NO scavenging, P-glycoprotein activity, and properties were performed. The levels of Caspase 3 and Caspase 9 were measured using ELISA to assess which pathways induced apoptosis by the tested compounds. On the chip, the synergistic effect of doxorubicin and the most active compound from the MM9 series on cells of the A375 melanoma line was determined.
RESULTS: All tested N\'-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with immunomodulatory activity show multidirectional antitumor activity on A375 melanoma lines with an affinity for P-glycoprotein, induction of free radical formation and generation of DNA damage leading to the death of cancer cells, as well as formation of complexes with DNA Topoisomerase II. Most of the tested compounds show pro-apoptotic activity. The most active compound in the series induces apoptosis in three distinct pathways and acts synergistically with doxorubicin.
CONCLUSIONS: The most active compound with immunomodulatory properties showed multidirectional antitumor activity against cells of the A375 melanoma line and also had a synergistic pro-apoptotic effect with doxorubicin, which may result in a reduction of this cytostatic dose with increased effectiveness.
摘要：
背景：黑色素瘤是一种高度侵袭性的肿瘤，恶性程度高，癌细胞快速获得耐药性。
方法：首先对一系列具有免疫调节特性的异恶唑化合物进行生物学研究。在MTT测试中24小时孵育期后,该测定评估了施用异恶唑化合物后NHDF和A375细胞培养物的生存力。ROS和NO清除分析，P-糖蛋白活性，和性能进行了。使用ELISA测量半胱天冬酶3和半胱天冬酶9的水平以评估哪些途径通过测试化合物诱导细胞凋亡。在芯片上,确定了多柔比星和来自MM9系列的最具活性的化合物对A375黑素瘤系的细胞的协同作用。
结果：所有测试的5-氨基-N的N'-取代衍生物，具有免疫调节活性的3-二甲基-1,2-恶唑-4-碳酰肼对A375黑色素瘤系具有多向抗肿瘤活性，对P-糖蛋白具有亲和力，诱导自由基形成和DNA损伤的产生，导致癌细胞死亡，以及与DNA拓扑异构酶II形成复合物。大多数测试化合物显示促凋亡活性。系列中最具活性的化合物在三种不同的途径中诱导细胞凋亡,并与多柔比星协同作用。
结论：具有免疫调节特性的最具活性的化合物对A375黑素瘤细胞系的细胞显示出多向抗肿瘤活性，并且与多柔比星具有协同促凋亡作用，这可能导致这种细胞抑制剂量的减少与增加的有效性。
方法：首先对一系列具有免疫调节特性的异恶唑化合物进行生物学研究。
结果：所有测试的5-氨基-N的N'-取代衍生物，
结论：具有免疫调节特性的最具活性的化合物对A375黑素瘤细胞系的细胞显示出多向抗肿瘤活性，并且与多柔比星具有协同促凋亡作用，
