Program in Cell Cycle and Cancer Biology, Oklahoma Medical Research Foundation, 825, NE 13th Street, Oklahoma City, OK 73104, USA.
Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcicki Street, 60-781 Poznań, Poland.
Molecules. 2023 Jul 30;28(15):5759. doi: 10.3390/molecules28155759.
HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates of non-steroidal anti-inflammatory drugs (NSAIDs)-Ibuprofen and Ketoprofen-with oleanolic acid oximes derivatives (OAO) were synthesized, and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells, and HCC-derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells, treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB, it was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivative conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.
HCC 是一种高度侵袭性的恶性肿瘤，治疗选择有限。在这项研究中，我们合成了非甾体抗炎药（NSAIDs）-布洛芬和酮洛芬与齐墩果酸肟衍生物（OAO）的新型缀合物，并评估了它们作为调节与 HCC 发病机制相关的信号通路的调节剂在正常 THLE-2 肝细胞和 HCC 衍生的 HepG2 细胞中的活性。结果表明，与 OAO 衍生物缀合可降低两种细胞系中母体化合物的细胞毒性。在 THLE-2 细胞中，与缀合物的处理导致 Nrf2-ARE 途径的激活增加。在 HepG2 细胞中观察到相反的效果。在 NF-κB 的后期减少时，观察到 MAPK 信号通路（AKT、ERK、p38、p70S6K 和 JNK）的调制。此外，STAT3、STAT5 和 CREB 转录因子的蛋白水平也因 IBU 和 KET-OAO 衍生物缀合物的处理而显著降低。最活跃的是与 OAO-吗啡啉缀合的缀合物。总的来说，这项研究的结果表明，IBU-OAO 和 KET-OAO 衍生物缀合物调节参与肝癌发展的关键信号通路。它们对特定信号通路的影响因缀合物的结构而异。由于 IBU 和 KET 与 OAO 衍生物的缀合降低了它们的细胞毒性，因此缀合物可以被认为是预防肝癌的良好候选物。
