Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Ankara, Turkey.
Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey.
Fundam Clin Pharmacol. 2023 Jun;37(3):557-565. doi: 10.1111/fcp.12876. Epub 2023 Jan 30.
Chemotherapy with targeted drugs is the first line therapy option for acute and chronic myeloid leukemia. However, hematopoietic stem cell transplantation may be used in high-risk patients or patients with failed responses to chemo drugs. Discovery and development of more effective new agents with lower side effects is the main aim of leukemia treatment. In this study, a novel retinoid compound with tetrahydronaphthalene ring was synthesized and evaluated for anticancer activity in human chronic and acute myeloid leukemia cell lines K562 and HL-60. Novel N-(1H-indol-1-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide was synthesized based on molecular hybridization of the two different bioactive structures retinoid head and indole. The effects of the synthesized carboxamide compound, which was referred to as compound 5, were determined in K562 chronic myeloid leukemia and HL-60 acute myeloid leukemia cell lines and L929 fibroblast cell line, which served as a control. Colorimetric MTT and caspase3 activity tests, flow cytometry, western blot, and microscopic examinations were used to evaluate biological activity. Compound 5 more effectively induced cell death in HL60 cells in comparison to K562 cells and L929 fibroblast cells. Therefore, further mechanism of cell death was investigated in HL60 cell line. It was found that compound 5 induced remarkable cytotoxicity, caspase3 activation, and PARP fragmentation in HL60 cells. Flow cytometric staining showed that the percentage of cells arrested in G0/G1 was also increased with compound 5 treatment. Important modulator proteins of cell proliferation p-ERK, p-AKT, and p-m-TOR were also found to be inhibited with compound 5 treatment. Collectively, our results reveal compound 5, which is a novel indole retinoid compound as a potential active agent for the treatment of acute promyelocytic leukemia.
化疗联合靶向药物是急性和慢性髓性白血病的一线治疗选择。然而，对于高危患者或化疗药物反应不佳的患者，可能会采用造血干细胞移植。发现和开发具有更低副作用的更有效的新型药物是白血病治疗的主要目标。在这项研究中，合成了一种具有萘环的新型维甲酸化合物，并在人慢性和急性髓性白血病细胞系 K562 和 HL-60 中评估了其抗癌活性。新型 N-(1H-吲哚-1-基)-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-甲酰胺是基于维甲酸头部和吲哚这两种不同生物活性结构的分子杂交合成的。将所合成的酰胺化合物（称为化合物 5）作用于 K562 慢性髓性白血病和 HL-60 急性髓性白血病细胞系和 L929 成纤维细胞系（作为对照），并测定其效果。采用比色 MTT 和 caspase3 活性检测、流式细胞术、western blot 和显微镜检查来评估其生物学活性。与 K562 细胞和 L929 成纤维细胞相比，化合物 5 更有效地诱导 HL60 细胞死亡。因此，在 HL60 细胞系中进一步研究了细胞死亡的机制。结果发现，化合物 5 诱导 HL60 细胞产生明显的细胞毒性、caspase3 激活和 PARP 片段化。流式细胞术染色显示，用化合物 5 处理后，G0/G1 期细胞的比例也增加。细胞增殖的重要调节蛋白 p-ERK、p-AKT 和 p-m-TOR 也发现被化合物 5 抑制。总之，我们的结果揭示了化合物 5 作为一种潜在的急性早幼粒细胞白血病治疗活性药物，是一种新型的吲哚维甲酸化合物。
