Huang Gongchao, Zhang Wenqin, Tian Hongqi
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China.
Shanghai Kechow Pharma, Inc., Shanghai 201203, China.
Asian Biomed (Res Rev News). 2023 Oct 26;17(5):230-237. doi: 10.2478/abm-2023-0064. eCollection 2023 Oct.
Non-small cell lung cancer (NSCLC) has a poor prognosis and usually presents resistance against radiotherapy. MEK inhibitors have been proven to possess a radiosensitization effect. The compound KZ-001 as a particular MEK inhibitor is superior to the listed MEK inhibitor AZD6244.
To investigate whether KZ-001 could enhance the radiosensitivity of NSCLC cell lines in vitro.
MTT and colony formation assay were used to evaluate the radiosensitivity effect of KZ-001. Immunofluorescence, cell cycle, apoptosis staining, and western blot experiments were used to explore the radiosensitivity mechanism.
KZ-001 significantly decreased A549 cell viability at 6 Gy and 8 Gy radiation doses and caused the radiosensitivity at 1 Gy, 4 Gy, and 6 Gy in colony formation experiments. The A549 apoptosis ratio induced by irradiation (IR) combined with KZ-001 increased significantly in comparison with that by IR monotherapy (10.57% vs. 6.23%, = 0.0055). The anti-apoptosis marker Bcl-XL was found downregulated in KZ-001 and IR-treated A549/H460 cells, but apoptosis marker Bax was downregulated in H460. Extracellular regulated protein kinases (ERK1/2) phosphorylation of H460 cells could be blocked both by IR alone and IR combined with KZ-001. IR combined with KZ-001 is able to inhibit ERK activation of A549 cells apparently. KZ-001 increased the proportion of G2 phase in irradiated cells from 21.24% to 32.22%. KZ-001 could also significantly increase the double-strand break damage cell ratio to more than 30% compared to the irradiation alone group.
MEK1/2 inhibitor KZ-001 is a potential radiosensitizer for clinical applications.
非小细胞肺癌（NSCLC）预后较差，通常对放疗产生抵抗。MEK抑制剂已被证明具有放射增敏作用。化合物KZ-001作为一种特殊的MEK抑制剂，优于已上市的MEK抑制剂AZD6244。
研究KZ-001在体外是否能增强NSCLC细胞系的放射敏感性。
采用MTT法和集落形成试验评估KZ-001的放射增敏作用。通过免疫荧光、细胞周期、凋亡染色及蛋白质免疫印迹实验探究放射增敏机制。
在6 Gy和8 Gy辐射剂量下，KZ-001显著降低A549细胞活力；在集落形成实验中，KZ-001在1 Gy、4 Gy和6 Gy剂量下产生放射增敏作用。与单纯放疗相比，放疗（IR）联合KZ-001诱导的A549细胞凋亡率显著增加（10.57%对6.23%，P = 0.0055）。在KZ-001与放疗处理的A549/H460细胞中，抗凋亡标志物Bcl-XL表达下调，但在H460细胞中凋亡标志物Bax表达下调。单独放疗以及放疗联合KZ-001均可阻断H460细胞外调节蛋白激酶（ERK1/2）的磷酸化。放疗联合KZ-001能够显著抑制A549细胞的ERK激活。KZ-001使受照射细胞的G2期比例从21.24%增加到32.22%。与单纯放疗组相比，KZ-001还可使双链断裂损伤细胞比例显著增加至30%以上。
MEK1/2抑制剂KZ-001是一种具有临床应用潜力的放射增敏剂。
