Article(id=1209198307381998338, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1209198303988813828, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.06.03, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1613664000000, receivedDateStr=2021-02-19, revisedDate=1621008000000, revisedDateStr=2021-05-15, acceptedDate=null, acceptedDateStr=null, onlineDate=1766224942297, onlineDateStr=2025-12-20, pubDate=1624809600000, pubDateStr=2021-06-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766224942297, onlineIssueDateStr=2025-12-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766224942297, creator=13701087609, updateTime=1766224942297, updator=13701087609, issue=Issue{id=1209198303988813828, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='6', pageStart='531', pageEnd='636', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766224941489, creator=13701087609, updateTime=1766225124231, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1209199070531424860, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1209198303988813828, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1209199070531424861, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1209198303988813828, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=545, endPage=549, ext={EN=ArticleExt(id=1209198309525287763, articleId=1209198307381998338, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect of propofol on the anti-tumor effect of oxaliplatin in the transplanted tumor of human gastric cancer in BALB/c mice, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the effect of propofol on human gastric cancer transplant BALB/c mice model treated with oxaliplatin. Methods We established a human gastric cancer model in the BALB/c mice using MGC 803 cells subcutaneous transplantation. Then the mice were randomly divided into control group (n=6), propofol group (n=6, 5 mg/kg propofol), oxaliplatin group (n=6, 6 mg/kg oxaliplatin), and propofol with oxaliplatin group (n=6, 5 mg/kg propofol+6 mg/kg oxaliplatin). The mice in each group received a total of 3 consecutive drug administrations through intraperitoneal injection once every 3 days. Mice were sacrificed two days after the last injection. Blood samples were then collected. The tumor volume and mass tumor inhibition rates were analyzed, respectively. The histological features of the tumor were evaluated with HE staining. The expression levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum were quantified using ELISA. In addition, the expression levels of epidermal growth factor (EGF), matrix metal protease-2 (MMP-2) and MMP-9 proteins in transplanted tumor tissue were quantified using ELISA. Results Compared with control group, the volume tumor inhibition rates (F=248.717, P<0.05) and mass tumor inhibition rates (F=376.205, P<0.05) of propofol group, oxaliplatin group, and propofol+oxaliplatin group were significantly reduced. The tumor volume inhibition rate and mass tumor inhibition rate of propofol+oxaliplatin group were significantly lower than those of oxaliplatin group, and the differences were statistically significant (tumor volume inhibition rate: 82.44%±4.69% vs.47.18%±5.71%, P<0.05; mass tumor inhibition rate: 77.95%±3.64% vs. 46.43%±3.99%, P<0.05). Compared with control group, cancer cell volume was reduced to varying degrees as well as the number of cancer cells was decreased in the remaining drug-treated groups using HE staining. In addition, the most significant decrease in cancer cell number happened in propofol+oxaliplatin group.The cell nucleus shrinks into a uniform blue-black dense body with an increased cytoplasmic density, increased cancer cell nuclear fragments, and large areas of necrosis. ELISA results showed that the levels of TNF-α and IL-6 in serum and EGF, MMP-2 and MMP-9 in transplanted tumor tissues of propofol group, oxaliplatin group and propofol+oxaliplatin group were significantly lower than those in control group, and those in propofol+oxaliplatin group were significantly lower than those in oxaliplatin group, and the differences were statistically significant (P<0.05). Conclusion Propofol can increase the sensitivity of gastric cancer cells to oxaliplatin, inhibit the proliferation, invasion and metastasis of gastric cancer cells, and enhance the anti-tumor effect of oxaliplatin.The mechanism may be related to the inhibition of inflammatory response by propofol and the regulation of EGF expression.

, correspAuthors=Wei Yue, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨丙泊酚对奥沙利铂在人胃癌BALB/c小鼠移植瘤模型中抗肿瘤作用的影响。方法 建立人胃癌MGC 803细胞BALB/c小鼠皮下移植瘤模型,随机分为对照组(n=6)、丙泊酚组(n=6,5 mg/kg丙泊酚)、奥沙利铂组(n=6,6 mg/kg奥沙利铂)与丙泊酚+奥沙利铂组(n=6,5 mg/kg丙泊酚+6 mg/kg奥沙利铂),每3d腹腔注射给药1次,连续3次。停药2 d后,采集血样并处死小鼠,取移植瘤称重,并测量移植瘤的长径和短径,计算小鼠移植瘤体积抑瘤率和质量抑瘤率。采用HE染色观察移植瘤细胞的形态学变化;ELISA法测定血清中肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)以及移植瘤组织中表皮细胞生长因子(EGF)、基质金属蛋白酶-2(MMP-2)、MMP-9的表达水平。结果 与对照组相比,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组移植瘤的体积(F=248.717,P<0.05)、质量(F=376.205,P<0.05)均有不同程度的降低。丙泊酚+奥沙利铂组移植瘤的体积抑瘤率、质量抑瘤率明显高于奥沙利铂组,差异有统计学意义(体积抑瘤率:82.44%±4.69% vs. 47.18%±5.71%,P<0.05;质量抑瘤率:77.95%±3.64% vs. 46.43%±3.99%,P<0.05)。HE染色显示,与对照组相比,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组移植瘤细胞的生长受到不同程度的抑制,癌细胞数量减少;其中丙泊酚+奥沙利铂组癌细胞数量减少最为明显,细胞核固缩为均一的蓝黑色致密物,胞质密度增大,核碎片增多,可见大面积坏死。ELISA检测结果显示,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组小鼠血清中TNF-α、IL-6以及移植瘤组织中EGF、MMP-2、MMP-9的表达水平均明显低于对照组,且丙泊酚+奥沙利铂组低于奥沙利铂组,差异有统计学意义(P<0.05)。结论 丙泊酚可抑制胃癌细胞的增殖、侵袭和转移,并增高胃癌细胞对奥沙利铂的化疗敏感性,增强奥沙利铂的抗肿瘤作用,其机制可能与丙泊酚抑制炎症反应及调控EGF的表达有关。

, correspAuthors=岳维, authorNote=null, correspAuthorsNote=
岳维,E-mail:
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姜敬男,硕士研究生,主要从事伤害性信号转导与器官损伤方面的研究

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姜敬男,硕士研究生,主要从事伤害性信号转导与器官损伤方面的研究

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姜敬男,硕士研究生,主要从事伤害性信号转导与器官损伤方面的研究

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A. 对照组;B. 丙泊酚组;C. 奥沙利铂组;D. 丙泊酚+奥沙利铂组

, figureFileSmall=T+psizgJdcOqvH5iAtEs6Q==, figureFileBig=VjYTFb+6krJOHpWa7IegkQ==, tableContent=null), ArticleFig(id=1209198313258218485, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1209198307381998338, language=EN, label=Tab.1, caption=

Comparison of tumor inhibition rate in each group ($\bar{x}±s$, n=6)

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组别移植瘤体积(mm3)体积抑瘤率(%)移植瘤质量(mg)质量抑瘤率(%)
对照组140.38±7.530269.08±11.190
丙泊酚组102.95±8.10(1)26.66±5.77(1)205.53±13.19(1)23.61±4.90(1)
奥沙利铂组74.15±8.02(1)47.18±5.71(1)144.15±10.73(1)46.43±3.99(1)
丙泊酚+奥沙利铂组24.65±6.59(1)(2)82.44±4.69(1)(2)59.35±9.79(1)(2)77.95±3.64(1)(2)
), ArticleFig(id=1209198313350493179, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1209198307381998338, language=CN, label=表1, caption=

各组小鼠移植瘤抑瘤率比较($\bar{x}±s$,n=6)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别移植瘤体积(mm3)体积抑瘤率(%)移植瘤质量(mg)质量抑瘤率(%)
对照组140.38±7.530269.08±11.190
丙泊酚组102.95±8.10(1)26.66±5.77(1)205.53±13.19(1)23.61±4.90(1)
奥沙利铂组74.15±8.02(1)47.18±5.71(1)144.15±10.73(1)46.43±3.99(1)
丙泊酚+奥沙利铂组24.65±6.59(1)(2)82.44±4.69(1)(2)59.35±9.79(1)(2)77.95±3.64(1)(2)
), ArticleFig(id=1209198313413407745, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1209198307381998338, language=EN, label=Tab.2, caption=

Comparison of the levels of TNF-α and IL-6 in serum and EGF, MMP-2 and MMP-9 in transplanted tumor tissues of transplanted tumor mice (pg/ml, $\bar{x}±s$, n=6)

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组别TNF-αIL-6EGFMMP-2MMP-9
对照组103.64±9.27226.93±17.09330.79±31.94544.24±50.39451.47±44.48
丙泊酚组89.31±7.32(1)197.98±15.40(1)273.35±27.21(1)426.15±31.32(1)342.54±29.65(1)
奥沙利铂组74.37±5.07(1)155.95±15.62(1)236.48±24.88(1)334.19±29.38(1)242.97±20.90(1)
丙泊酚+奥沙利铂组57.62±4.71(1)(2)80.26±8.75(1)(2)141.69±12.41(1)(2)138.61±15.26(1)(2)116.97±13.17(1)(2)
), ArticleFig(id=1209198313522458626, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1209198307381998338, language=CN, label=表2, caption=

各组小鼠血清中TNF-α、IL-6以及移植瘤组织中EGF、MMP-2、MMP-9的表达水平比较(pg/ml,$\bar{x}±s$,n=6)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别TNF-αIL-6EGFMMP-2MMP-9
对照组103.64±9.27226.93±17.09330.79±31.94544.24±50.39451.47±44.48
丙泊酚组89.31±7.32(1)197.98±15.40(1)273.35±27.21(1)426.15±31.32(1)342.54±29.65(1)
奥沙利铂组74.37±5.07(1)155.95±15.62(1)236.48±24.88(1)334.19±29.38(1)242.97±20.90(1)
丙泊酚+奥沙利铂组57.62±4.71(1)(2)80.26±8.75(1)(2)141.69±12.41(1)(2)138.61±15.26(1)(2)116.97±13.17(1)(2)
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丙泊酚对奥沙利铂抗人胃癌BALB/c小鼠移植瘤作用的影响
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姜敬男 1 , 岳维 2, *
解放军医学杂志 | 基础研究 2021,46(6): 545-549
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解放军医学杂志 | 基础研究 2021, 46(6): 545-549
丙泊酚对奥沙利铂抗人胃癌BALB/c小鼠移植瘤作用的影响
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姜敬男1, 岳维2, *
作者信息
  • 1山西医科大学麻醉学院,太原 030000
  • 2山西医科大学第二医院麻醉科,太原 030000
  • 姜敬男,硕士研究生,主要从事伤害性信号转导与器官损伤方面的研究

通讯作者:

岳维,E-mail:
Effect of propofol on the anti-tumor effect of oxaliplatin in the transplanted tumor of human gastric cancer in BALB/c mice
Jing-Nan Jiang1, Wei Yue2, *
Affiliations
  • 1College of Anesthesiology, Shanxi Medical University, Taiyuan 030000, China
  • 2Department of Anesthesiology, the Second Hospital of Shanxi Medical University, Taiyuan 030000, China
出版时间: 2021-06-28 doi: 10.11855/j.issn.0577-7402.2021.06.03
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目的 探讨丙泊酚对奥沙利铂在人胃癌BALB/c小鼠移植瘤模型中抗肿瘤作用的影响。方法 建立人胃癌MGC 803细胞BALB/c小鼠皮下移植瘤模型,随机分为对照组(n=6)、丙泊酚组(n=6,5 mg/kg丙泊酚)、奥沙利铂组(n=6,6 mg/kg奥沙利铂)与丙泊酚+奥沙利铂组(n=6,5 mg/kg丙泊酚+6 mg/kg奥沙利铂),每3d腹腔注射给药1次,连续3次。停药2 d后,采集血样并处死小鼠,取移植瘤称重,并测量移植瘤的长径和短径,计算小鼠移植瘤体积抑瘤率和质量抑瘤率。采用HE染色观察移植瘤细胞的形态学变化;ELISA法测定血清中肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)以及移植瘤组织中表皮细胞生长因子(EGF)、基质金属蛋白酶-2(MMP-2)、MMP-9的表达水平。结果 与对照组相比,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组移植瘤的体积(F=248.717,P<0.05)、质量(F=376.205,P<0.05)均有不同程度的降低。丙泊酚+奥沙利铂组移植瘤的体积抑瘤率、质量抑瘤率明显高于奥沙利铂组,差异有统计学意义(体积抑瘤率:82.44%±4.69% vs. 47.18%±5.71%,P<0.05;质量抑瘤率:77.95%±3.64% vs. 46.43%±3.99%,P<0.05)。HE染色显示,与对照组相比,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组移植瘤细胞的生长受到不同程度的抑制,癌细胞数量减少;其中丙泊酚+奥沙利铂组癌细胞数量减少最为明显,细胞核固缩为均一的蓝黑色致密物,胞质密度增大,核碎片增多,可见大面积坏死。ELISA检测结果显示,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组小鼠血清中TNF-α、IL-6以及移植瘤组织中EGF、MMP-2、MMP-9的表达水平均明显低于对照组,且丙泊酚+奥沙利铂组低于奥沙利铂组,差异有统计学意义(P<0.05)。结论 丙泊酚可抑制胃癌细胞的增殖、侵袭和转移,并增高胃癌细胞对奥沙利铂的化疗敏感性,增强奥沙利铂的抗肿瘤作用,其机制可能与丙泊酚抑制炎症反应及调控EGF的表达有关。

丙泊酚  /  奥沙利铂  /  胃癌  /  移植瘤

Objective To explore the effect of propofol on human gastric cancer transplant BALB/c mice model treated with oxaliplatin. Methods We established a human gastric cancer model in the BALB/c mice using MGC 803 cells subcutaneous transplantation. Then the mice were randomly divided into control group (n=6), propofol group (n=6, 5 mg/kg propofol), oxaliplatin group (n=6, 6 mg/kg oxaliplatin), and propofol with oxaliplatin group (n=6, 5 mg/kg propofol+6 mg/kg oxaliplatin). The mice in each group received a total of 3 consecutive drug administrations through intraperitoneal injection once every 3 days. Mice were sacrificed two days after the last injection. Blood samples were then collected. The tumor volume and mass tumor inhibition rates were analyzed, respectively. The histological features of the tumor were evaluated with HE staining. The expression levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum were quantified using ELISA. In addition, the expression levels of epidermal growth factor (EGF), matrix metal protease-2 (MMP-2) and MMP-9 proteins in transplanted tumor tissue were quantified using ELISA. Results Compared with control group, the volume tumor inhibition rates (F=248.717, P<0.05) and mass tumor inhibition rates (F=376.205, P<0.05) of propofol group, oxaliplatin group, and propofol+oxaliplatin group were significantly reduced. The tumor volume inhibition rate and mass tumor inhibition rate of propofol+oxaliplatin group were significantly lower than those of oxaliplatin group, and the differences were statistically significant (tumor volume inhibition rate: 82.44%±4.69% vs.47.18%±5.71%, P<0.05; mass tumor inhibition rate: 77.95%±3.64% vs. 46.43%±3.99%, P<0.05). Compared with control group, cancer cell volume was reduced to varying degrees as well as the number of cancer cells was decreased in the remaining drug-treated groups using HE staining. In addition, the most significant decrease in cancer cell number happened in propofol+oxaliplatin group.The cell nucleus shrinks into a uniform blue-black dense body with an increased cytoplasmic density, increased cancer cell nuclear fragments, and large areas of necrosis. ELISA results showed that the levels of TNF-α and IL-6 in serum and EGF, MMP-2 and MMP-9 in transplanted tumor tissues of propofol group, oxaliplatin group and propofol+oxaliplatin group were significantly lower than those in control group, and those in propofol+oxaliplatin group were significantly lower than those in oxaliplatin group, and the differences were statistically significant (P<0.05). Conclusion Propofol can increase the sensitivity of gastric cancer cells to oxaliplatin, inhibit the proliferation, invasion and metastasis of gastric cancer cells, and enhance the anti-tumor effect of oxaliplatin.The mechanism may be related to the inhibition of inflammatory response by propofol and the regulation of EGF expression.

propofol  /  oxaliplatin  /  gastric cancer  /  transplanted tumor
姜敬男, 岳维. 丙泊酚对奥沙利铂抗人胃癌BALB/c小鼠移植瘤作用的影响. 解放军医学杂志, 2021 , 46 (6) : 545 -549 . DOI: 10.11855/j.issn.0577-7402.2021.06.03
Jing-Nan Jiang, Wei Yue. Effect of propofol on the anti-tumor effect of oxaliplatin in the transplanted tumor of human gastric cancer in BALB/c mice[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (6) : 545 -549 . DOI: 10.11855/j.issn.0577-7402.2021.06.03
胃癌是我国最常见的消化道恶性肿瘤,也是全球范围内癌症相关死亡的第三大原因。手术切除治疗是胃癌最主要的治疗手段,但多数患者发现时已属中晚期,术后复发率及转移率均较高,仅通过手术治疗难以达到最佳效果,因此多依赖于化学药物治疗[1]。近年来研究发现,胃癌细胞对化疗药的耐药性逐渐增强[2-3],化疗耐药性是癌症治疗中的关键问题[4]。因此,寻找新的药物增强胃癌细胞对化疗药物的敏感性,对改善化疗疗效及提高患者术后生存率具有重要的临床意义。丙泊酚是一种常用的静脉麻醉药,广泛应用于肿瘤切除术中。越来越多的证据表明,丙泊酚除具有麻醉作用外,还具有抗肿瘤作用。既往体外实验研究发现,丙泊酚可抑制胃癌、肺癌、肝癌等多种癌细胞的增殖、侵袭、转移,诱导癌细胞凋亡[5-7]。但目前丙泊酚是否会对胃癌患者的化疗疗效产生影响尚未明确。本研究建立人胃癌BALB/c小鼠移植瘤模型,探讨丙泊酚对奥沙利铂抗肿瘤作用的影响,以期为胃癌的临床治疗提供参考。
RPMI 1640培养液(E600028-0500)、胎牛血清(E510002-0100)购自上海生工生物工程有限公司;丙泊酚(MB1613)购自大连美仑生物技术有限公司;奥沙利铂(O8390)、二甲基亚砜(DMSO,D8371)购自北京索莱宝生物有限公司;肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、表皮细胞生长因子(EGF)、基质金属蛋白酶-2(MMP-2)、MMP-9 ELISA试剂盒购自江苏酶免生物科技公司。CO2恒温细胞培养箱购自美国Thermo Forna公司;CK-40型倒置显微镜、BX-51型荧光显微镜购自日本TKO光学仪器株式会社;RM2245石蜡切片机购自德国Leica公司;Novapath酶标仪购自美国Bio-Rad公司。
BALB/c小鼠40只,由山西医科大学实验动物中心提供,雌雄各半,体重20~22 g,在(22±2)℃、50%±10%湿度条件下适应性喂养1周后进行实验。人胃癌MGC 803细胞株(货号:CX0213)购自武汉博士德生物工程有限公司。
接种前1 d,小鼠腹腔注射环磷酰胺200 mg/kg、地塞米松40 mg/kg,以抑制机体的免疫反应。参考文献[8]的方法制备人胃癌MGC 803细胞小鼠移植瘤模型。人胃癌MGC 803细胞株于含10%胎牛血清、10 U/L青-链霉素的RPMI 1640培养液中培养,置于37℃、5% CO2培养箱中。取对数生长期细胞,用0.25%胰酶消化吹打成单细胞悬液,1000 r/min离心5 min,用PBS稀释,制备成单细胞悬液(1×107个/ml)。在小鼠右侧腹股沟处接种0.2 ml胃癌细胞悬液,12 d后观察成瘤情况(腹股沟处出现长径约6 mm的皮下结节,提示移植瘤模型建立成功)。
共14只雄性、13只雌性小鼠成瘤,弃掉生长状态相对较差(如毛发不光滑、活动度降低等)的雄性2只、雌性1只,共24只成瘤小鼠进入实验,随机分为对照组、丙泊酚组(5 mg/kg丙泊酚)、奥沙利铂组(6 mg/kg奥沙利铂)与丙泊酚+奥沙利铂组(5 mg/kg丙泊酚+6 mg/kg奥沙利铂),每组6只,雌雄各半。每3d腹腔注射给药1次,连续3次。给药后小鼠生长状态良好,无不良反应,未见死亡现象。
停药2 d后麻醉小鼠,采用心脏取血法采集血样后处死,剥离肿瘤组织,测量肿瘤大小,记录肿瘤的长径(a)和短径(b),瘤体积=a×b2/2。各组瘤体积取平均值,计算抑瘤率。体积抑瘤率(%)=(对照组平均瘤体积—实验组平均瘤体积)/对照组平均瘤体积×100%。称取各组移植瘤重量,取平均值,计算抑瘤率。质量抑瘤率(%)=(对照组平均瘤重量—实验组平均瘤重量)/对照组平均瘤重量×100%。采集的血样和肿瘤组织保存于–70℃冰箱备测。
肿瘤组织于4%甲醛溶液中固定24 h,乙醇梯度脱水,石蜡包埋,制作石蜡切片,然后经脱蜡、水化后,采用HE染色,中性树脂胶封片,光学显微镜下观察细胞形态学变化。
严格按照ELISA试剂盒说明书步骤测定各组血清中TNF-α、IL-6的表达水平。取肿瘤组织,匀浆,按照ELISA试剂盒说明书步骤测定各组移植瘤组织中EGF、MMP-2、MMP-9的表达水平。
采用SPSS 25.0软件进行统计分析。符合正态分布的计量资料以$\bar{x}±s$表示,多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。P<0.05为差异有统计学意义。
与对照组相比,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组小鼠移植瘤的体积、质量均有不同程度的降低(移植瘤体积:F=248.717,P<0.05;移植瘤质量:F=376.205,P<0.05)。与奥沙利铂组相比,丙泊酚+奥沙利铂组小鼠移植瘤的体积抑瘤率、质量抑瘤率明显增高,差异有统计学意义(P<0.05)(表1)。
HE染色结果显示,对照组移植瘤细胞增生分裂活跃,癌细胞呈圆形或椭圆形,细胞核大深染,不规则。丙泊酚组癌细胞数量减少,核分裂象减少,部分癌细胞变性、体积缩小。奥沙利铂组癌细胞核分裂象减少,部分癌细胞由片状变性趋近于片状坏死。丙泊酚+奥沙利铂组癌细胞数量明显减少,增生分裂受到抑制,癌细胞体积明显减小,细胞核固缩为均一的蓝黑色致密物,胞质密度增大;癌细胞核碎片增多,可见大面积坏死(图1)。
ELISA检测结果显示,丙泊酚组、奥沙利铂组及丙泊酚+奥沙利铂组小鼠血清中TNF-α、IL-6以及移植瘤组织中EGF、MMP-2和MMP-9的表达水平明显低于对照组,且丙泊酚+奥沙利铂组低于奥沙利铂组,差异有统计学意义(P<0.05,表2)。
胃癌已成为威胁人类健康和生存的主要疾病,也是我国癌症死亡的重要原因之一。目前胃癌主要采用手术切除治疗,但进展期胃癌患者由于已发生转移,需要进行化疗以杀灭原位残留的癌细胞及远处转移的癌细胞。作为第三代铂类抗癌药物,奥沙利铂常用于胃癌的治疗,其作用机制主要为铂原子与肿瘤细胞DNA快速结合形成链内交联,阻断DNA的复制和转录,从而发挥抗肿瘤作用[9]。尽管奥沙利铂对晚期胃癌的疗效明显,但大多数患者最终仍会对其产生耐药性[10]。因此,提高胃癌细胞对奥沙利铂化疗的敏感性,增强奥沙利铂的抗肿瘤作用以改善胃癌患者的预后,是目前亟须解决的问题。本研究采用丙泊酚联合奥沙利铂对人胃癌BALB/c小鼠移植瘤模型进行干预,结果显示,丙泊酚组、奥沙利铂组移植瘤的质量和体积均明显低于对照组,表明两种药物均可抑制肿瘤的生长。丙泊酚与奥沙利铂联合组的抗肿瘤效应明显高于奥沙利铂组,表明丙泊酚不仅可抑制胃癌细胞的生长,还可增强奥沙利铂的抗肿瘤效应。
炎症反应被认为是癌症发生发展中的一个重要特征[11]。部分研究者认为,与癌症相关的炎症反应主要与肿瘤部位发生的局部免疫反应有关,而这种炎症反应常有助于肿瘤的发展[12]。炎性细胞因子可通过多种途径促进肿瘤的发展,包括对肿瘤细胞的直接影响、与趋化因子的相互作用、刺激上皮细胞间质转化等[13]。TNF-α是重要的炎性介质之一,可促进多种炎性因子的释放,从而加剧炎症反应[14]。IL-6是一种多功能促炎细胞因子,与胃癌的发生发展及预后密切相关[15]。有研究发现,TNF-α、IL-6在癌性环境下可被诱导并促进肿瘤细胞的生长增殖[16-17]。因此,减少炎性因子的分泌可能是抑制胃癌进展的有效方法。本研究结果表明,丙泊酚可抑制炎性介质TNF-α、IL-6等的释放,并显著增强奥沙利铂对TNF-α、IL-6的抑制作用,提示丙泊酚增强奥沙利铂抗肿瘤作用的机制之一可能是其抑制了炎性因子的促肿瘤细胞增殖作用。
有研究发现,EGF在胃癌组织中过表达,可通过自分泌和旁分泌的方式作用于癌组织,与表皮生长因子受体(EGFR)结合可促进胃癌的生长和转移[18]。此外,EGF还可诱导胃癌细胞中VEGF mRNA的表达,促进新生血管生长,加速肿瘤细胞的侵袭和转移。基质金属蛋白酶(MMPs)是肿瘤细胞侵袭、转移过程中的关键酶,主要包括MMP-2和MMP-9,二者被激活后可以形成Ⅳ型胶原酶,降解基底膜和细胞外基质,促进肿瘤细胞的浸润和转移,是反映肿瘤侵袭和转移能力的重要指标[19]。体外实验发现,丙泊酚能够抑制胃癌细胞SGC-7901的侵袭和转移,而该过程与其调控MMP的表达水平有关[20]。本研究结果显示,与对照组相比,丙泊酚组、奥沙利铂组移植瘤组织中EGF、MMP-2、MMP-9的表达水平均明显降低,且丙泊酚与奥沙利铂联合用药可进一步降低EGF、MMP-2、MMP-9的表达,提示丙泊酚可通过抑制胃癌细胞的侵袭和转移来增强奥沙利铂的抗肿瘤作用。
目前,丙泊酚增强奥沙利铂对胃癌细胞化疗疗效的具体机制尚不明确,有关丙泊酚对癌症患者化疗疗效影响的研究较少。共济失调素-2样蛋白(ATXN2L)是Ataxin家族中的一员,Ataxin家族蛋白主要在神经系统疾病中发挥重要作用,但近年来其在肿瘤领域的研究也成为了热点[21]。研究发现,使用不同浓度的EGF处理胃癌MGC 803细胞,细胞中ATXN2L mRNA和蛋白的表达量随着EGF浓度的增高而升高;当沉默ATXN2L后,EGF促进胃癌细胞侵袭和转移的能力被部分逆转,由此可见,EGF可通过上调ATXN2L的表达,促进胃癌细胞的侵袭和转移,从而降低胃癌细胞对奥沙利铂的敏感性[22]。本研究结果显示,丙泊酚可通过抑制EGF的表达来增强奥沙利铂的抗肿瘤作用,由此推测,丙泊酚可能通过EGF/ATXN2L途径来提高胃癌细胞对奥沙利铂的敏感性,其具体机制尚待进一步研究。
综上所述,丙泊酚可以抑制胃癌细胞的增殖、侵袭和转移,并提高胃癌细胞对奥沙利铂的化疗敏感性,从而增强奥沙利铂的抗肿瘤作用,其机制可能与丙泊酚抑制炎症反应及调控EGF的表达水平有关。该结果为丙泊酚用于改善胃癌患者对奥沙利铂的化疗耐药性提供了理论依据。
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2021年第46卷第6期
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doi: 10.11855/j.issn.0577-7402.2021.06.03
  • 接收时间:2021-02-19
  • 首发时间:2025-12-20
  • 出版时间:2021-06-28
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  • 收稿日期:2021-02-19
  • 修回日期:2021-05-15
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Youth Project of National Natural Science Foundation of China(34100940)
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    1山西医科大学麻醉学院,太原 030000
    2山西医科大学第二医院麻醉科,太原 030000

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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