Xi Pan, Ma Xiaojuan, Hu Fuquan, Li Liang, Liu Huijuan, Zhou Jing, Wu Wenan
Department of Radiotherapy, Shaanxi Provincial Cancer Hospital, Xi'an, China.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Cell Biol Int. 2023 Nov;47(11):1825-1834. doi: 10.1002/cbin.12073. Epub 2023 Aug 6.
Gemcitabine (GEM)-based chemotherapy represents the first choice for locally unresectable advanced pancreatic cancer, while the benefit is limited due to acquired chemoresistance or drug delivery insufficiency. Hyperthermia treatment potentially improves the clinical efficacy of GEM. However, the underlying mechanism is incompletely revealed. Our study aims to investigate the effect and involved mechanism of thermochemotherapy on cell survival. Pancreatic cancer cells PANC-1 and ASPC-1 were either treated with GEM or thermochemotherapy, then cell viability, apoptosis, migration, invasion, reactive oxygen species (ROS) production, and Sp1 expression were evaluated. The results showed that GEM dose and time-dependently affected cell viability, and 30 μM GEM achieved favorable effect in suppressing cancer cell growth. Meanwhile, hyperthermia preconditioning (43°C for 60 min) 24 h before GEM treatment yielded superior effect than other treatment sequence. GEM caused significant cell apoptosis and proapoptotic genes of both cancer cells, and thermochemotherapy further promoted apoptosis and genes transcription, accompanied by excessive ROS production. Thermochemotherapy was superior to GEM in suppressing cell migration and invasion of pancreatic cancer cells. Meanwhile, GEM significantly reduced Sp1 mRNA and protein and its downstream gene Cox-2, and thermochemotherapy further suppressed their expressions. ROS elimination with N-acetyl-l-cysteine notably neutralizes the suppressive effect of GEM and thermochemotherapy on cell growth and expressions of Sp1 and Cox-2. In conclusion, thermochemotherapy inhibited pancreatic cell viability, migration and invasion, and promoted cell apoptosis by inducing excessive ROS production, which subsequently suppressed Sp1 expression and the downstream Cox-2.
基于吉西他滨（GEM）的化疗是局部不可切除的晚期胰腺癌的首选治疗方法，然而，由于获得性化疗耐药或药物递送不足，其疗效有限。热疗有可能提高GEM的临床疗效。然而，其潜在机制尚未完全阐明。本研究旨在探讨热化疗对细胞存活的影响及其相关机制。对胰腺癌细胞PANC-1和ASPC-1分别进行GEM治疗或热化疗，然后评估细胞活力、凋亡、迁移、侵袭、活性氧（ROS）生成及Sp1表达。结果显示，GEM对细胞活力的影响具有剂量和时间依赖性，30μM GEM在抑制癌细胞生长方面取得了良好效果。同时，在GEM治疗前24小时进行热预处理（43°C，60分钟）比其他治疗顺序产生了更好的效果。GEM可导致两种癌细胞显著凋亡及促凋亡基因表达，热化疗进一步促进凋亡和基因转录，并伴有过量ROS生成。热化疗在抑制胰腺癌细胞迁移和侵袭方面优于GEM。同时，GEM显著降低Sp1 mRNA和蛋白及其下游基因Cox-2的表达，热化疗进一步抑制它们的表达。用N-乙酰-L-半胱氨酸消除ROS可显著抵消GEM和热化疗对细胞生长以及Sp1和Cox-2表达的抑制作用。总之，热化疗通过诱导过量ROS生成抑制胰腺细胞活力、迁移和侵袭，并促进细胞凋亡，随后抑制Sp1表达及其下游的Cox-2。
