Superior Effect of the Combination of Carbon-Ion Beam Irradiation and 5-Fluorouracil on Colorectal Cancer Stem Cells in vitro and in vivo.
Superior Effect of the Combination of Carbon-Ion Beam Irradiation and 5-Fluorouracil on Colorectal Cancer Stem Cells in vitro and in vivo.
复制标题
DOI：
10.2147/ott.s276035
复制
发表时间：
2020
影响因子：
4
通讯作者：
Tsujii H
中科院分区：
文献类型：
--
作者：
Koom WS;Sai S;Suzuki M;Fujimori A;Yamada S;Tsujii H
本研究的目的是探讨碳离子束联合5-氟尿嘧啶（5-FU）在靶向结直肠癌干细胞（CSCs）方面是否优于碳离子束单独照射。用碳离子束单独或联合5-FU治疗人类结直肠癌（CRC）细胞HCT116和HT29。进行细胞活力测定、集落和球体形成测定、凋亡测定以及凋亡和自噬相关基因表达的实时荧光定量PCR分析。碳离子束照射剂量依赖性地降低CRC细胞活力，与5-FU联合照射时，细胞杀伤效果显著增强。碳离子束照射联合5-FU可显著增加凋亡细胞的百分比。碳离子束单独照射可显著诱导Bax、Bcl2、Beclin1、ATG7等凋亡和自噬相关基因的表达，与5-FU联合照射可进一步增强这些基因的表达。碳离子束联合5-FU可显著抑制CD133+细胞亚群的球形形成能力。组织病理学上，与单独碳离子束照射相比，碳离子束和5-FU联合照射破坏了更多的异种移植肿瘤细胞，导致坏死、空化和纤维化增加。综上所述，碳离子束联合5-FU有可能通过诱导细胞凋亡和自噬增加来杀死包括csc在内的CRC细胞。
The aim of this study was to investigate whether carbon-ion beam irradiation in combination with 5-fluorouracil (5-FU) is superior to carbon-ion beam irradiation alone in targeting colorectal cancer stem-like cells (CSCs). Human colorectal cancer (CRC) cells, HCT116 and HT29, were treated with carbon-ion beam irradiation alone or in combination with 5-FU. Cell viability assay, colony and spheroid formation assay, apoptotic assay, and quantitative real-time PCR analysis of apoptosis- and autophagy-related gene expression were performed. Carbon-ion beam irradiation dose-dependently decreased CRC cell viability and showed significantly enhanced cell killing effect when combined with 5-FU. Carbon-ion beam irradiation in combination with 5-FU significantly increased the percentage of apoptotic cells. The expression of some apoptotic and autophagy-related genes such as Bax, Bcl2, Beclin1 and ATG7 was significantly induced by carbon-ion beam irradiation alone and was further enhanced when the beam was combined with 5-FU. The spheroid forming capacity of CD133+ cell subpopulations was significantly inhibited by carbon-ion beam in combination with 5-FU. Histopathologically, the combination of carbon-ion beam irradiation and 5-FU destroyed more xenograft tumor cells, and resulted in increased necrosis, cavitation, and fibrosis, compared to carbon-ion beam irradiation alone. In conclusion, carbon-ion beam treatment combined with 5-FU has the potential to kill CRC cells including CSCs by inducing increased apoptosis and autophagy.