Kim Shin, Kim Dong Eun, Kang Hyunsu, Hong Victor Sukbong, Jeon Jieun, Lee Jinho, Kim Ki-Suk, Park Jong-Wook
Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea.
Institute of medical science, Keimyung University, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea.
J Cancer. 2023 Jul 16;14(12):2224-2235. doi: 10.7150/jca.85650. eCollection 2023.
The anti-proliferative effects of a newly developed 3-acyl-5-aryl-3,5-diaminoindazole analog, KMU-191, have been previously evaluated in various cancer cells. However, the detailed anti-cancer molecular mechanisms of KMU-191 remain unknown. In this study, we investigated anti-cancer mechanisms by which KMU-191 regulates apoptosis-related genes in human clear cell renal cell carcinoma Caki cells. KMU-191 induced poly ADP-ribose polymerase cleavage and caspase-dependent apoptosis. In addition, KMU-191 induced down-regulation of the long form of cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the transcriptional level as well as that of long form of myeloid cell leukemia (Mcl-1 (L)) and B-cell lymphoma-extra large at the post-transcriptional level. Furthermore, KMU-191-induced apoptosis was closely associated with the Mcl-1 (L) down-regulation, but also partially associated with c-FLIP (L) down-regulation. In contrast, KMU-191 up-regulated p53, which is closely related to KMU-191-induced apoptosis. Although KMU-191 showed cytotoxicity of normal cells, it unusually did not induce cardiotoxicity. Taken together, these results suggest that a multi-target small molecule, 3-acyl-5-aryl-3,5-diaminoindazole analog, KMU-191 is a potential anti-cancer agent that does not induce cardiotoxicity.
一种新开发的3-酰基-5-芳基-3,5-二氨基吲唑类似物KMU-191的抗增殖作用此前已在多种癌细胞中进行了评估。然而，KMU-191详细的抗癌分子机制仍不清楚。在本研究中，我们研究了KMU-191在人透明细胞肾细胞癌Caki细胞中调节凋亡相关基因的抗癌机制。KMU-191诱导聚ADP-核糖聚合酶裂解和半胱天冬酶依赖性凋亡。此外，KMU-191在转录水平诱导细胞FADD样白细胞介素-1β转化酶抑制蛋白（c-FLIP(L)）长形式的下调，以及在转录后水平诱导髓样细胞白血病长形式（Mcl-1(L)）和B细胞淋巴瘤-特大号的下调。此外，KMU-191诱导的凋亡与Mcl-1(L)下调密切相关，但也部分与c-FLIP(L)下调相关。相反，KMU-191上调了与KMU-191诱导的凋亡密切相关的p53。虽然KMU-191对正常细胞显示出细胞毒性，但它异常地不诱导心脏毒性。综上所述，这些结果表明，一种多靶点小分子3-酰基-5-芳基-3,5-二氨基吲唑类似物KMU-191是一种潜在的不诱导心脏毒性的抗癌药物。
