异硫氰酸苄酯联合索拉非尼治疗未分化甲状腺癌机制探讨

doi:10.11958/20250340

天津医药 ›› 2025, Vol. 53 ›› Issue (5): 449-455.doi: 10.11958/20250340

• 细胞与分子生物学 • 下一篇

异硫氰酸苄酯联合索拉非尼治疗未分化甲状腺癌机制探讨

马春梅¹^,²(), 于鹏³, 张其程⁴, 杨磊⁵, 李棣华⁵, 谭建¹, 孟召伟¹^,^△()

1 天津医科大学总医院核医学科，天津市功能影像重点实验室和天津市影像医学研究所（邮编300052）
2 华北理工大学附属医院影像中心
3 核医学科
4 天津医科大学总医院，天津市肺癌转移与肿瘤微环境重点实验室，天津市肺癌研究所
5 天津市南开医院，天津市急腹症相关器官损伤及ITCWM修复重点实验室，急性腹部疾病研究所

收稿日期:2025-01-22 修回日期:2025-03-13 出版日期:2025-05-15 发布日期:2025-05-28
通讯作者: △ E-mail：zmeng@tmu.edu.cn
作者简介:马春梅（1984），女，博士在读，主要从事肿瘤与血管病变影像学诊断方面研究。E-mail：karles@126.com
基金资助:
国家自然科学基金资助项目(81971650);天津市科委基金资助项目(21JCYBJC01820);天津市医学重点学科（专科）建设项目(TJYXZDXK-001A)

Mechanism study of benzyl isothiocyanate combined with sorafenib in the treatment of anaplastic thyroid cancer

MA Chunmei¹^,²(), YU Peng³, ZHANG Qicheng⁴, YANG Lei⁵, LI Dihua⁵, TAN Jian¹, MENG Zhaowei¹^,^△()

1 Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin 300052, China
2 Imaging Center
3 Department of Nuclear Medicine, North China University of Science and Technology Affiliated Hospital
4 Tianjin Medical University General Hospital, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute
5 Tianjin Nankai Hospital, Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases

Received:2025-01-22 Revised:2025-03-13 Published:2025-05-15 Online:2025-05-28
Contact: △ E-mail：zmeng@tmu.edu.cn

马春梅, 于鹏, 张其程, 杨磊, 李棣华, 谭建, 孟召伟. 异硫氰酸苄酯联合索拉非尼治疗未分化甲状腺癌机制探讨[J]. 天津医药, 2025, 53(5): 449-455.

MA Chunmei, YU Peng, ZHANG Qicheng, YANG Lei, LI Dihua, TAN Jian, MENG Zhaowei. Mechanism study of benzyl isothiocyanate combined with sorafenib in the treatment of anaplastic thyroid cancer[J]. Tianjin Medical Journal, 2025, 53(5): 449-455.

摘要/Abstract

摘要：

目的探讨异硫氰酸苄酯（BITC）联合索拉非尼（Sor）治疗未分化甲状腺癌（ATC）的机制。方法将0、20、30、40和50 μmol/L Sor作用于2种ATC细胞株8505C和CAL-62，采用CCK-8法检测细胞存活率。通过计算联合用药指数测定BITC和Sor的联合用药剂量。将CAL-62和8505C分别用10 μmol/L BITC（BITC组）、10 μmol/L Sor（Sor组）、10 μmol/L BITC和10 μmol/L Sor（BITC+Sor组）联合应用处理24 h，对照组不作处理。CCK-8法检测BITC和Sor的联合用药对ATC细胞活力的影响；流式细胞术分析细胞凋亡情况；Western blot检测核因子（NF）-κB、自噬微管相关蛋白轻链3抗体（LC3B）Ⅱ及Beclin-1表达量；实时荧光定量PCR检测LC3B mRNA水平；将CAL-62细胞皮下注射到小鼠体内形成肿瘤模型，分别腹腔注射BITC（100 mg/kg）、Sor灌胃（30 mg/kg）、BITC与Sor联合处理隔天给药共21 d，Western blot检测肿瘤组织NF-κB、LC3BⅡ及Beclin-1的表达。结果 Sor以浓度依赖性的方式抑制CAL-62和8505C细胞的活力。BITC 10 μmol/L和Sor 10 μmol/L时联合用药指数为0.710，两药有适度协同作用。在8505C和CAL-62细胞中，与对照组相比，BITC组和Sor组细胞活力、Beclin-1及NF-κB蛋白表达水平降低，凋亡率、LC3B mRNA、LC3BⅡ蛋白表达水平升高（P<0.05）；与BITC组和Sor组比较，BITC+Sor组细胞活力、Beclin-1及NF-κB蛋白表达降低，凋亡率、LC3B mRNA、LC3BⅡ蛋白表达水平升高（P<0.05）。小鼠移植瘤模型中，BITC+Sor组与BITC组和Sor组比较，LC3BⅡ表达增加，Beclin-1及NF-κB表达水平、肿瘤体积和质量降低（P<0.05）。结论 BITC和Sor联合应用在体外和体内均可通过NF-κB通路抑制ATC细胞，诱导自噬，促进凋亡。

关键词: 甲状腺癌, 未分化, 索拉非尼, 自噬, NF-κB, 异硫氰酸苄酯

Abstract:

Objective To investigate the mechanism of benzyl isothiocyanate (BITC) combined with sorafenib (Sor) in the treatment of anaplastic thyroid cancer (ATC). Methods Two ATC cell lines, 8505C and CAL-62, were treated with Sor at concentrations of 0, 20, 30, 40, and 50 μmol/L. The cell survival rate was assessed using CCK-8 assay. The combined dose of BITC and Sor was determined by calculating combination index (CI). CAL-62 and 8505C cells were exposed to 10 μmol/L BITC (BITC group), 10 μmol/L Sor (Sor group), or a combination of 10 μmol/L BITC and 10 μmol/L Sor (BITC+Sor group) for 24 hours. The control group was not treated. The effects of Sor and BITC on ATC cell viability were evaluated using the CCK-8 method. Apoptosis was analyzed via flow cytometry. Western blot assay was employed to detect the protein expression levels of LC3B Ⅱ, Beclin-1 and nuclear factor (NF)-κB. Real-time fluorescence quantitative PCR was used to quantify the mRNA levels of LC3B. Additionally, CAL-62 cells were subcutaneously injected into mice to establish tumor xenograft model. Mice were treated with BITC (100 mg/kg, intraperitoneal injection), Sor (30 mg/kg, intragastric administration) or a combination of BITC and Sor every other day for 21 days. Finally, the expression levels of LC3B Ⅱ, Beclin-1 and NF-κB in tumor tissue were analyzed by Western blot assay. Results Sor significantly inhibited the viability of CAL-62 and 8505C cells in a concentration-dependent manner. The combination index (CI) was 0.710 at BITC 10 μmol/L and Sor 10 μmol/L, indicating a moderate synergistic effect between the two drugs. In both 8505C and CAL-62 cells, compared with the control group, treatment with BITC or Sor resulted in the decreased cell viability, as well as reduced expression levels of Beclin-1 and NF-κB proteins (P<0.05), and the apoptosis rate, LC3B mRNA and LC3B Ⅱ protein expression levels were significantly increased (P<0.05). When BITC and Sor were combined, the cell viability, Beclin-1 and NF-κB protein expressions were further reduced compared to either drug alone, while the apoptosis rate, LC3B mRNA and LC3B Ⅱ protein expression levels were significantly elevated (P<0.05). In the mouse xenograft tumor model, the BITC+Sor group exhibited increased LC3B Ⅱ expression, along with decreased Beclin-1 and NF-κB expression levels, tumor volume and tumor mass compared to the BITC or Sor groups (P<0.05). Conclusion The combination of BITC and Sor can inhibit ATC cells through NF-κB pathway, induce autophagy and promote apoptosis in vitro and in vivo.

Key words: thyroid carcinoma, anaplastic, sorafenib, autophagy, NF-kappa B, benzyl isothiocyanate

中图分类号:

R969.2

图/表 13

表1 引物序列

Tab.1 Primer sequence

基因名称	引物序列（5'→3'）	产物大小/bp
LC3B	上游：AACATGAGCGAGTTGGTCAAG 下游：GCTCGTAGATGTCCGCGAT	127
GAPDH	上游：GGAGCGAGATCCCTCCAAAAT 下游：GGCTGTTGTCATACTTCTCATGG	197

图1 Sor对2种ATC细胞活力的影响 A：8505C细胞；B：CAL-62细胞。

Fig.1 Effect of Sor on two kinds of ATC cells

图2 Sor与BITC联合应用药效作用评估 A：两药联合的CI数据（Fa为抑制率）；B：两药联合细胞抑制率为50%时的相关数据（ED50为半数有效量）。

Fig.2 Efficacy evaluation of Sor combined with BITC

表2 各组ATC细胞活力比较（n=3,%,$\bar{x}±s$）

Tab.2 Comparison of ATC cell activity between the four groups

组别	8505C	CAL-62
对照组	100.00±0.00	100.00±0.00
BITC组	83.24±1.43^a	82.64±0.90^a
Sor组	79.78±1.12^a	82.85±0.25^a
BITC+Sor组	66.48±0.80^abc	66.22±1.27^abc
F	579.069^＊＊	920.836^＊＊

表3 各组ATC细胞凋亡率的比较（n=3,%,$\bar{x}±s$）

Tab.3 Comparison of apoptosis rate of ATC cells between the four groups

组别	8505C	CAL-62
对照组	4.91±0.60	3.35±1.04
BITC组	14.71±1.43^a	17.98±2.84^a
Sor组	12.14±2.09^a	17.35±1.81^a
BITC+Sor组	39.49±3.97^abc	37.77±9.96^abc
F	118.068^＊＊	21.512^＊＊

图3 各组8505C细胞凋亡情况

Fig.3 Apoptosis of 8505C cells in each group

图4 各组CAL-62细胞凋亡情况

Fig.4 Apoptosis of CAL-62 cells in each group

表4 各组LC3B mRNA表达水平比较（n=3,$\bar{x}±s$）

Tab.4 Effect of BITC and Sor combined treatment on LC3B gene expression in ATC cells

组别	8505C	CAL-62
对照组	1.02±0.01	1.00±0.73
BITC组	9.00±0.89^a	8.54±0.73^a
Sor组	8.00±0.55^a	9.27±1.47^a
BITC+Sor组	40.28±3.40^abc	44.16±0.28^abc
F	289.683^＊＊	1 615.110^＊＊

表5 各组LC3B Ⅱ、Beclin-1及NF-κB蛋白表达水平比较（n=3,$\bar{x}±s$）

Tab.5 Comparison of expression levels of LC3B, Beclin-1 and NF-κB protein between the four groups

组别	8505C
组别	LC3BⅡ	Beclin-1	NF-κB
对照组	0.35±0.08	1.19±0.11	1.14±0.12
BITC组	0.81±0.03^a	0.88±0.07^a	0.93±0.08^a
Sor组	0.82±0.06^a	0.79±0.10^a	0.92±0.10^a
BITC+Sor组	1.31±0.33^abc	0.54±0.08^abc	0.58±0.04^abc
F	15.474^＊＊	24.406^＊＊	26.066^＊＊
组别	CAL-62
组别	LC3BⅡ	Beclin-1	NF-κB
对照组	0.28±0.04	1.12±0.10	1.19±0.17
BITC组	0.85±0.13^a	0.81±0.09^a	0.90±0.01^a
Sor组	0.73±0.06^a	0.73±0.02^a	0.88±0.07^a
BITC+Sor组	2.09±0.28^abc	0.53±0.07^abc	0.61±0.07^abc
F	72.391^＊＊	29.713^＊＊	17.641^＊＊

图5 8505C和CAL-62细胞中LC3BⅡ、Beclin-1及NF-κB蛋白免疫印迹图

Fig.5 Western blot results of LC3B Ⅱ, Beclin-1 and NF-κB protein in 8505C and CAL-62 cells

图6 裸鼠移植瘤体质量与体积变化 A：裸鼠体质量变化；B：各组离体移植瘤。

Fig.6 Changes in volume and body weight of transplanted tumor in nude mice

表6 各组裸鼠移植瘤质量、体积及各项蛋白表达水平比较（$\bar{x}±s$）

Tab.6 Comparison of weight, volume and protein expression of transplanted tumor between the four groups of nude mice

组别	移植瘤质量/mg（n=5）			移植瘤体积/mm³（n=5）
对照组	73.70±21.54			171.43±59.75
BITC组	43.40±15.73^a			103.19±17.55^a
Sor组	43.60±17.74^a			102.02±21.61^a
BITC+Sor组	14.00±3.54^abc			53.12±15.29^abc
F	11.321^＊＊			10.329^＊＊
组别		蛋白（n=3）
组别		LC3BⅡ	Beclin-1		NF-κB
对照组		0.28±0.01	1.08±0.06		1.12±0.11
BITC组		0.70±0.08^a	0.87±0.04^a		0.91±0.02^a
Sor组		0.57±0.04^a	0.81±0.07^a		0.86±0.063^a
BITC+Sor组		1.09±0.20^abc	0.53±0.11^abc		0.62±0.11^abc
F		27.520^＊＊	27.012^＊＊		19.378^＊＊

图7 BITC与Sor对裸鼠移植瘤中LC3BⅡ、Beclin-1及NF-κB表达的影响

Fig.7 Effects of BITC and Sor on expression of LC3BII, Beclin-1 and NF-κB in transplanted tumor of nude mice

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异硫氰酸苄酯联合索拉非尼治疗未分化甲状腺癌机制探讨

Mechanism study of benzyl isothiocyanate combined with sorafenib in the treatment of anaplastic thyroid cancer

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