Fang Zhenghuan, Jung Kyung Hee, Lee Ji Eun, Cho Jinhyun, Lim Joo Han, Hong Soon-Sun
Department of Biomedical Sciences, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 22332, Republic of Korea.
Department of Internal Medicine, Inha University Hospital, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon 22332, Republic of Korea.
Transl Oncol. 2020 Nov;13(11):100833. doi: 10.1016/j.tranon.2020.100833. Epub 2020 Jul 23.
Head and neck cancer (HNC) is characterized with multiple aberrations in cell cycle pathways, including amplification of cyclin D1. Palbociclib (PAL), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has been reported to regulate cell cycle progression in HNC. However, recent studies have revealed the acquired resistance of certain cells to PAL through activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Therefore, we investigated whether the inhibition of MEK/ERK pathway by trametinib (TRA) may overcome the limited efficacy of PAL in HNC. We evaluated the effect of PAL alone and in combination with TRA on the viability of HNC cells, and found that the combination treatment synergistically inhibited the proliferation of HNC cells. The combination treatment induced G0/G1 cell cycle arrest and apoptotic cell death. In particular, apoptosis mediated by the combination treatment was accompanied with an increase in caspase-3 activity and the number of TUNEL-positive apoptotic cells. These results were consistent with the decrease in cell cycle progression and mitogen-activated protein kinase (MAPK) pathway activation. In a xenograft mouse model of HNC, PAL and TRA synergistically inhibited tumor growth and enhanced tumor cell apoptosis, consistent with the increase in the number of TUNEL-positive cells. The anti-proliferative effects were evident in tumor tissues subjected to the combination treatment as compared with those treated with single drug. Taken together, our study demonstrates that the combination of PAL and TRA exerts synergistic anticancer effects and inhibits cell cycle check points and MEK/ERK pathway in HNC, suggestive of their potential application for HNC treatment.
头颈癌（HNC）的特征是细胞周期通路存在多种异常，包括细胞周期蛋白D1的扩增。哌柏西利（PAL）是一种细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂，据报道可调节HNC中的细胞周期进程。然而，最近的研究表明某些细胞通过激活丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）通路对PAL产生获得性耐药。因此，我们研究了曲美替尼（TRA）抑制MEK/ERK通路是否可以克服PAL在HNC中有限的疗效。我们评估了PAL单独使用以及与TRA联合使用对HNC细胞活力的影响，发现联合治疗可协同抑制HNC细胞的增殖。联合治疗诱导G0/G1期细胞周期停滞和凋亡性细胞死亡。特别是，联合治疗介导的凋亡伴随着半胱天冬酶-3活性的增加和TUNEL阳性凋亡细胞数量的增加。这些结果与细胞周期进程的减少和丝裂原活化蛋白激酶（MAPK）通路的激活一致。在HNC的异种移植小鼠模型中，PAL和TRA协同抑制肿瘤生长并增强肿瘤细胞凋亡，这与TUNEL阳性细胞数量的增加一致。与单药治疗的肿瘤组织相比，联合治疗的肿瘤组织中抗增殖作用明显。综上所述，我们的研究表明，PAL和TRA联合使用具有协同抗癌作用，并抑制HNC中的细胞周期检查点和MEK/ERK通路，提示它们在HNC治疗中的潜在应用价值。
