Page 60 - 《中国药房》2020年22期

hepatocarcinoma model；at the same time，2 protection groups were given CUR or HZC（80 mg/kg）intraperitoneally，twice a
day，for consecutive 12 weeks. During medication，the change of body weight and death of rats were recorded. Twenty four weeks
later，liver index of rats was calculated and appearance was observed；the number of cancer nodules was counted；HE staining was
used to observe the pathological changes of liver tissue and calculate the nuclear division index of hepatocarcinoma； the
proliferating cell nuclear antigen（PCNA）index was detected by immunohistochemistry. RESULTS：CUR and HZC could increase
the inhibitory rate of HepG2 cells（P＜0.05），and increased the percentage at G0/G1 phase and apoptotic rate of HepG2 cells（P＜
0.05）. CUR and HZC could significantly decrease the protein expression of p-JAK2，p-STAT3，Bcl-2 and Bcl-xl，while increased
the protein expression of Bax，Cyt-c，Caspase-9，Caspase-3 and PAPR（P＜0.05）. Above effects of HZC were significantly better
than those of CUR（P＜0.05）. The results of animal experiment showed that there was no death，no liver canceration and no
pathological changes in liver appearance and tissue section of the three control groups；there was no statistical significance in body
weight and its increased weight，liver index，nuclear division index of carcinoma or PCNA index（P＞0.05）. Compared with model
group， survival rate of rats were increased significantly in CUR protection group and HZC protection group， while
hepatocarcinoma incidence and the number of cancer nodules were decreased significantly （P＜0.05）；body weight and its
increased weight were increased significantly，while liver index，nuclear division index of carcinoma and PCNA index were
decreased significantly（P＜0.05）. There were some pathological changes in liver appearance and tissue section；cancerous lesions
with focal necrosis or cancerous lesions with patchy necrosis were observed. There was no statistical significance in the
improvement of above indexes in 2 protection groups（P＞0.05）. CONCLUSIONS：HZC could inhibit the proliferation and induce
apoptosis of HepG2 cells by inhibiting JAK2/STAT3 signaling pathway and regulating the activation of mitochondrial endogenous
pathway，which shows stronger anti-hepatocarcinoma effect in vitro than CUR. On the other hand，there was no significant
difference in the improvement of liver caner indexes in hepatic cancer model rats between HZC and CUR.
KEYWORDS Hepatocarcinoma；Curcumin；Hydrazinocurcumin；JAK2/STAT3 signaling pathway；HepG2 cells；Rats；Nuclear
division index；PCNA index

肝细胞癌（HCC）是世界上导致癌症死亡性相关疾 HepG2 细胞增殖、凋亡及相关蛋白表达的影响，以及对
病的第三大主要原因，每年约有70万新诊断病例，并有 二乙基亚硝胺（DEN）诱导的大鼠肝肿瘤的抑制作用，比
[1]
超过 25 万例死亡 。在肝癌早期，可以通过手术切除、 较两者的体内外抗肝癌作用，旨在为姜黄素类衍生物应
射频消融（RFA）和经导管动脉化疗栓塞（TACE）等方法 用于肝癌的临床治疗提供实验基础。
进行治疗，可能提供治愈的机会，但这只能在肿瘤病灶 O O
小、远离大血管且没有转移到肝外器官的特定患者中进
HO OH
行 。过去常用的全身化疗已被相关研究证实对肝癌患 OCH3 OCH3
[2]
者的治疗效果有限，且在临床对照试验中发现，其对正 A. CUR
N — NH
[3]
常细胞有害且容易使肿瘤细胞产生耐药性 。 H3CO OCH3
大量体外研究证明，姜黄素（Curcumin，CUR）在许 HO 3 OH
多肝癌细胞系中可以阻滞细胞周期，发挥细胞毒性作 B. HZC
[4]
用，并参与抑制细胞增殖和诱导细胞凋亡 。虽然，CUR 图1 CUR和HZC的结构式
具有很好的抗癌活性且无明显毒性，但临床前和临床研 Fig 1 Structure of CUR and HZC
究均表明，其在生理学条件下不稳定、生物利用度较差， 1 材料
[5]
故使得其在抗癌治疗中的应用受到了限制 。有研究指 1.1 仪器
出，对 CUR 进行结构类似物的合成改造是解决其生物 SW-CJ-2F 型超净工作台（上海苏净实业有限公
利用度差并保留或进一步提高其药效作用的一种方 司）；TC2323型CO2细胞培养箱（美国SHELLAB 公司）；
[6]
法 。联氨基姜黄素（Hydrazinocurcumin，HZC）是 CUR 30RF型低温高速离心机（德国Hettich公司）；TC20型细
的吡唑类衍生物（两者结构式见图 1），与 CUR 相比， 胞计数仪（美国Bio-Rad公司）；AE31倒置相差显微镜及
HZC具有更好的水溶性和稳定性，且具有较高的细胞通 照相系统（德国 Motic 公司）；Accuri C6 型流式细胞仪
透性、抗肿瘤活性、生物利用度以及良好的肠道通透 （美国BD公司）；ELX800型酶标仪（美国Bio Tek公司）；
性 ；其对多种肿瘤细胞系都具有毒性，尤其是对人肝癌 DYCZ-24DN 型垂直电泳仪（北京市六一仪器厂）；BOX
[7]
HepG2 细胞，在所有姜黄素类似物中，HZC 的半数有效 型成像分析系统（英国Syngene公司）；BS210S型电子天
浓度最低 ；此外，HZC能更有效地抑制信号转导及转录 平（德国Sartorius公司）。
[8]
激活蛋白3（STAT3）磷酸化、下调STAT3蛋白表达，从而 1.2 药品和试剂
抑制肿瘤细胞增殖、集落形成、迁移和侵袭并诱导其凋 CUR 原料药（批号：78246，纯度：99.5％）、DEN（批
亡 。基于此，本研究通过考察 HZC 和 CUR 对人肝癌 号：93861，纯度：＞99.0％）、DMEM培养基、MTT试剂均
[9]

·2742 · China Pharmacy 2020 Vol. 31 No. 22 中国药房 2020年第31卷第22期