姜黄素联合奥沙利铂抗结肠癌作用及其相关机制研究
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摘要
结肠癌是一种严重威胁人类生命和健康的恶性肿瘤，在西方发达国家，其发病率居恶性肿瘤的第2位，随着人们生活习惯和饮食结构的改变，我国结肠癌的发病率呈逐年递增趋势，发病递增速度为世界平均数的两倍，是中国发病率排第四位的恶性肿瘤性疾病。如何有效的预防和治疗结肠癌，成为医学界关注的热点之一。除了传统的手术、放疗与化疗外，寻找高效、低毒的药物和研究中西医结合治疗方案仍是目前结肠癌治疗中有待解决的问题。天然药物因其多靶点、多环节和多途径的抗肿瘤作用，日渐成为临床抗肿瘤药物研究的热点。
姜黄素是从草本植物姜黄的根茎中提取的一种天然多酚，药理作用广泛，抗癌是其主要作用之一。奥沙利铂是继顺铂和卡铂之后的第三代新型铂类抗癌药，具有广泛的抗肿瘤谱，是目前临床治疗结肠癌的常用药物。因此，在深入研究姜黄素的抗癌活性与作用机制的基础上，进一步探讨其与奥沙利铂联合的抗结肠癌作用，可为结肠癌综合治疗的临床应用提供技术基础。本研究以结肠癌细胞LoVo为体外实验对象，以结肠癌裸鼠移植瘤模型为体内实验对象，采用流式细胞术、透射电镜(TEM)、反转录-聚合酶链式反应(RT-PCR)、western blotting、免疫组织化学和免疫荧光细胞化学染色等技术研究了姜黄素联合奥沙利铂的体内外抗结肠癌作用及相关机制。主要研究结果总结如下：
1．姜黄素对不同组织来源的肿瘤细胞(LoVo， SW480， MCF-7， BGC-823和SMMC-7721)都有生长抑制作用，并呈剂量和时间依赖关系；其中对LoVo和MCF-7细胞的生长抑制较为明显，而对正常细胞HK-2只有超过48h、20μg/mL以上剂量时，对其生长有一定的抑制作用。提示姜黄素抑制细胞生长作用可能具有组织特异性，可能不具有明显的肿瘤细胞特异性。
2．姜黄素能显著抑制LoVo细胞生长、增殖，呈较好的浓度和时间效应关系；在处理24、48和72h时，姜黄素对LoVo细胞的半数抑制浓度(IC50)分别为12.70±0.06，8.80±0.50和4.97±0.71μg/mL；姜黄素能使LoVo细胞发生形态学改变，表现出典型的凋亡细胞特征；能阻滞细胞周期于S期，诱导LoVo细胞凋亡。
3．姜黄素可显著降低LoVo细胞线粒体膜电位，促使细胞色素c的释放，抑制Bcl-2、Bcl-xL、c-myc和survivin蛋白的表达，上调Bax、caspase-3和p53蛋白的表达，增加caspase-9的活性，通过线粒体途径诱导LoVo细胞凋亡。
4．姜黄素联合奥沙利铂能协同抑制LoVo细胞增殖，能使LoVo细胞发生明显的形态学改变，能阻滞细胞周期于S期，诱导大量肿瘤细胞死亡。
5．姜黄素协同奥沙利铂可显著降低LoVo细胞线粒体膜电位，激活caspase-3和caspase-9的表达，在mRNA水平上抑制Bcl-2和Bcl-xL表达、促进Bax表达，在蛋白水平抑制Bcl-2、c-myc和survivin蛋白的表达，促进Bax和caspase-3蛋白的表达。
6．50mg/kg剂量的姜黄素能抑制LoVo裸鼠移植瘤的生长，且与奥沙利铂联合应用对移植瘤生长抑制产生相加效应，肿瘤抑瘤率分别为59.47%和70.56%；姜黄素及联合处理组对荷瘤裸鼠的血液系统、肝肾器官未见毒性；姜黄素与奥沙利铂联合能干扰细胞周期，使其阻滞于S期，诱导大量肿瘤细胞凋亡和坏死。对荷瘤裸鼠肿瘤组织应用RT-PCR、western blotting和免疫组化技术阐明了姜黄素与奥沙利铂联合能显著抑制Bcl-xL、Bcl-2、c-myc和survivin表达、促进Bax表达，下调HSP70蛋白表达，激活caspase-3和PARP表达。
7．姜黄素能调节荷瘤裸鼠抗氧化体系。在体内，姜黄素单用及与奥沙利铂联合处理可显著提高移植瘤裸鼠血清T-SOD和T-AOC水平，降低血清MDA水平；可显著提高肝肾组织中T-SOD、T-AOC和GR水平；可显著提高脾脏T-AOC水平，对T-SOD无显著作用，姜黄素组的GR水平最高；姜黄素组及联合组均能降低裸鼠肿瘤组织T-AOC、T-SOD和GR水平；姜黄素组及联合组能显著降低荷瘤裸鼠血清LDH活性，姜黄素组AKP活性无显著变化，而联合组AKP表达显著提高。在体外，姜黄素对·OH、O2·-和DPPH自由基均有较强的清除能力。
总之，姜黄素可以通过细胞毒作用、诱导凋亡作用使肿瘤细胞生长停滞并逐渐走向死亡，与奥沙利铂联用对LoVo细胞生长具有协同抑制效应。姜黄素与奥沙利铂联合应用于结肠癌的治疗，既减轻了奥沙利铂的毒性，又增加了抗癌作用，并且未出现两药毒性重叠现象，提示姜黄素与奥沙利铂联合治疗结肠癌具有可行性，值得在临床推广应用。
Colon cancer is a serious threat to human life and health of malignant tumors, and itsincidence is ranked the second malignant tumors in western developed countries. With thepeople's living habits and diet changes, the incidence of colon cancer in China showed anincreasing trend, the incidence rate of increase is twice the world average, is ranked the fourthin the incidence of malignant diseases. How effective prevention and treatment of coloncancer has become one of the focus of attention of the medical profession. In addition to thetraditional surgery, radiotherapy and chemotherapy, to find efficient, low toxicity drugs andstudy combining traditional Chinese medicine and western medicine treatment is still to beresolved in the colon cancer treatment. Natural medicine because of its multi-target,multi-link and multi-channel anti-tumor effect, becoming a hot spot of the clinical anticancerdrug research.
Curcumin (diferuloylmethane) is a natural polyphenol extracted from the rhizomes of theplant Curcuma longa Linn. It has wide range of pharmacological effects, anti-cancer is one ofthe main function. Oxaliplatin is a third generation platinum anti-cancer drugs after cisplatinand carboplatin. It has a wide range of anti-tumor spectrum, and is commonly used drugs inthe clinical treatment of colon cancer. Therefore, in-depth study of the anti-cancer activity ofcurcumin and its mechanism, and further studying anti-colon cancer effect of combination ofcurcumin and oxaliplatin could establish some foundation for colon cancer treatment inclinical application. In this research, anti-tumoral effects and mechanism of combination ofcurcumin and oxaliplatin on human colon cancer cells in vitro and in vivo were investigatedwith colon cancer cells LoVo and colon cancer-bearing nude mice models through flowcytometry, transmission electron microscopy (TEM), reverse transcription-polymerase chainreaction (RT-PCR), western blotting, immunohistochemistry and immunofluorescencemethods. The main results as follow:
1. Curcumin could inhibit the growth of the tumor cells of different tissue origin (LoVo,SW480, MCF-7, BGC-823and SMMC-7721), has a dose-and time-dependent relationship;the growth of inhibition is more obvious in LoVo and MCF-7cells, while in normal cellsHK-2more than48h, when doses of more than20μg/mL, its growth has a certain inhibition.Suggesting that curcumin inhibition of cell growth may have tissue-specific, may not have asignificant tumor cell-specific.
2. Curcumin could significantly inhibit the growth and proliferation in LoVo cells, has abetter concentration-and time-dependent relationship; The inhibitory concentration50% (IC50) of curcumin were12.70±0.06,8.80±0.50and4.97±0.71μg/mL in LoVo cells at24,48and72h. Curcumin could make LoVo cell morphological changes, showing the typicalcharacteristics of apoptotic cells; arrest cell cycle at S phase, and induce apoptosis of LoVocells.
3. Curcumin can significantly reduce mitochondrial membrane potential, prompting therelease of cytochrome c, inhibition the expression of Bcl-2, Bcl-xL, c-myc and survivinprotein, up-regulation the expression of Bax, caspase-3and p53protein, increase the activityof caspase-9in LoVo cells, and induced apoptosis of LoVo cells through the mitochondrialpathway.
4. Combination of curcumin and oxaliplatin could synergistically inhibit proliferation ofLoVo cells, make the LoVo cells obvious morphological changes, arrest cell cycle at S phase,induce a large number of tumor cells death.
5. Combination of curcumin and oxaliplatin could synergistically reduce significantlymitochondrial membrane potential, activate the expression of caspase-3and caspase-9, inhibitthe expression of Bcl-2and Bcl-xL and promote the expression of Bax at the mRNA level,down-regulation the expression of Bcl-2, c-myc, and survivin protein, and promote theexpression of Bax and caspase-3at the protein level.
6.50mg/kg dose of curcumin can inhibit the growth of LoVo colonic xenografts in nudemice, and combination of curcumin and oxaliplatin group treatment could emerge additiveeffect on the inhibition of tumor growth, tumor inhibition rates were59.47%and70.56%,respectively. Curcumin group and combination of curcumin and oxaliplatin group treatmentdid not influence nude mice blood system, liver and kidney organs. Combination of curcuminand oxaliplatin group treatment could interfere with cell cycle arrest at S phase, inducingtumor cells apoptosis and necrosis. Using RT-PCR, western blotting andimmunohistochemistry to clarify the combination of curcumin and oxaliplatin treatment cansignificantly inhibit the Bcl-xL, Bcl-2, c-myc and survivin expression, promote the expressionof Bax, down-regulation the expression of HSP70protein, and activated caspase-3and PARPexpression in tumor tissue of tumor-bearing nude mice.
7. Curcumin could regulate the antioxidant system of colon cancer-bearing nude mice.Experiments in vivo showed that curcumin group and combination of curcumin andoxaliplatin group treatment could increase the levels of serum T-SOD and T-AOC, butdecrease the MDA level in tumor-bearing nude mice. They also improved the T-SOD, T-AOCand GR levels in liver and kidney of tumor-bearing nude mice, Furthermore, curcumin groupand combination of curcumin and oxaliplatin group treatment could increase the T-AOC level in spleen tissues, but not influence the T-SOD level in spleen, the GR level of spleen tissuewas the highest in curcumin group. To tumor tissues, curcumin group and combination ofcurcumin and oxaliplatin group treatment decreased T-AOC, T-SOD and GR levels. Besidesthat, the serum LDH level of tumor-bearing nude mice was suppressed by the treatment ofcurcumin group and combination of curcumin and oxaliplatin group. Curcumin grouptreatment could not influence the level of serum AKP, but combination of curcumin andoxaliplatin group treatment could increase the level of serum AKP significantly. Experimentsin vitro further showed that curcumin had strong effects on scavenging·OH radical, O2·-radical and DPPH radical.
In summary, curcumin could inhibit LoVo cells growth, induce LoVo cells arrest andapoptosis, Curcumin combination with oxaliplatin had a synergistic inhibitory effect on thegrowth of LoVo cells. Combination of curcumin and oxaliplatin used in the treatment of coloncancer, not only mitigated the toxicity of oxaliplatin, but also increased of anti-cancer effects,and did not find toxicity overlap of the two drugs. This suggested that the combination ofcurcumin and oxaliplatin treatment for colon cancer is feasible and worth of clinicalapplication.
姜黄素是从草本植物姜黄的根茎中提取的一种天然多酚，药理作用广泛，抗癌是其主要作用之一。奥沙利铂是继顺铂和卡铂之后的第三代新型铂类抗癌药，具有广泛的抗肿瘤谱，是目前临床治疗结肠癌的常用药物。因此，在深入研究姜黄素的抗癌活性与作用机制的基础上，进一步探讨其与奥沙利铂联合的抗结肠癌作用，可为结肠癌综合治疗的临床应用提供技术基础。本研究以结肠癌细胞LoVo为体外实验对象，以结肠癌裸鼠移植瘤模型为体内实验对象，采用流式细胞术、透射电镜(TEM)、反转录-聚合酶链式反应(RT-PCR)、western blotting、免疫组织化学和免疫荧光细胞化学染色等技术研究了姜黄素联合奥沙利铂的体内外抗结肠癌作用及相关机制。主要研究结果总结如下：
1．姜黄素对不同组织来源的肿瘤细胞(LoVo， SW480， MCF-7， BGC-823和SMMC-7721)都有生长抑制作用，并呈剂量和时间依赖关系；其中对LoVo和MCF-7细胞的生长抑制较为明显，而对正常细胞HK-2只有超过48h、20μg/mL以上剂量时，对其生长有一定的抑制作用。提示姜黄素抑制细胞生长作用可能具有组织特异性，可能不具有明显的肿瘤细胞特异性。
2．姜黄素能显著抑制LoVo细胞生长、增殖，呈较好的浓度和时间效应关系；在处理24、48和72h时，姜黄素对LoVo细胞的半数抑制浓度(IC50)分别为12.70±0.06，8.80±0.50和4.97±0.71μg/mL；姜黄素能使LoVo细胞发生形态学改变，表现出典型的凋亡细胞特征；能阻滞细胞周期于S期，诱导LoVo细胞凋亡。
3．姜黄素可显著降低LoVo细胞线粒体膜电位，促使细胞色素c的释放，抑制Bcl-2、Bcl-xL、c-myc和survivin蛋白的表达，上调Bax、caspase-3和p53蛋白的表达，增加caspase-9的活性，通过线粒体途径诱导LoVo细胞凋亡。
4．姜黄素联合奥沙利铂能协同抑制LoVo细胞增殖，能使LoVo细胞发生明显的形态学改变，能阻滞细胞周期于S期，诱导大量肿瘤细胞死亡。
5．姜黄素协同奥沙利铂可显著降低LoVo细胞线粒体膜电位，激活caspase-3和caspase-9的表达，在mRNA水平上抑制Bcl-2和Bcl-xL表达、促进Bax表达，在蛋白水平抑制Bcl-2、c-myc和survivin蛋白的表达，促进Bax和caspase-3蛋白的表达。
6．50mg/kg剂量的姜黄素能抑制LoVo裸鼠移植瘤的生长，且与奥沙利铂联合应用对移植瘤生长抑制产生相加效应，肿瘤抑瘤率分别为59.47%和70.56%；姜黄素及联合处理组对荷瘤裸鼠的血液系统、肝肾器官未见毒性；姜黄素与奥沙利铂联合能干扰细胞周期，使其阻滞于S期，诱导大量肿瘤细胞凋亡和坏死。对荷瘤裸鼠肿瘤组织应用RT-PCR、western blotting和免疫组化技术阐明了姜黄素与奥沙利铂联合能显著抑制Bcl-xL、Bcl-2、c-myc和survivin表达、促进Bax表达，下调HSP70蛋白表达，激活caspase-3和PARP表达。
7．姜黄素能调节荷瘤裸鼠抗氧化体系。在体内，姜黄素单用及与奥沙利铂联合处理可显著提高移植瘤裸鼠血清T-SOD和T-AOC水平，降低血清MDA水平；可显著提高肝肾组织中T-SOD、T-AOC和GR水平；可显著提高脾脏T-AOC水平，对T-SOD无显著作用，姜黄素组的GR水平最高；姜黄素组及联合组均能降低裸鼠肿瘤组织T-AOC、T-SOD和GR水平；姜黄素组及联合组能显著降低荷瘤裸鼠血清LDH活性，姜黄素组AKP活性无显著变化，而联合组AKP表达显著提高。在体外，姜黄素对·OH、O2·-和DPPH自由基均有较强的清除能力。
总之，姜黄素可以通过细胞毒作用、诱导凋亡作用使肿瘤细胞生长停滞并逐渐走向死亡，与奥沙利铂联用对LoVo细胞生长具有协同抑制效应。姜黄素与奥沙利铂联合应用于结肠癌的治疗，既减轻了奥沙利铂的毒性，又增加了抗癌作用，并且未出现两药毒性重叠现象，提示姜黄素与奥沙利铂联合治疗结肠癌具有可行性，值得在临床推广应用。
Colon cancer is a serious threat to human life and health of malignant tumors, and itsincidence is ranked the second malignant tumors in western developed countries. With thepeople's living habits and diet changes, the incidence of colon cancer in China showed anincreasing trend, the incidence rate of increase is twice the world average, is ranked the fourthin the incidence of malignant diseases. How effective prevention and treatment of coloncancer has become one of the focus of attention of the medical profession. In addition to thetraditional surgery, radiotherapy and chemotherapy, to find efficient, low toxicity drugs andstudy combining traditional Chinese medicine and western medicine treatment is still to beresolved in the colon cancer treatment. Natural medicine because of its multi-target,multi-link and multi-channel anti-tumor effect, becoming a hot spot of the clinical anticancerdrug research.
Curcumin (diferuloylmethane) is a natural polyphenol extracted from the rhizomes of theplant Curcuma longa Linn. It has wide range of pharmacological effects, anti-cancer is one ofthe main function. Oxaliplatin is a third generation platinum anti-cancer drugs after cisplatinand carboplatin. It has a wide range of anti-tumor spectrum, and is commonly used drugs inthe clinical treatment of colon cancer. Therefore, in-depth study of the anti-cancer activity ofcurcumin and its mechanism, and further studying anti-colon cancer effect of combination ofcurcumin and oxaliplatin could establish some foundation for colon cancer treatment inclinical application. In this research, anti-tumoral effects and mechanism of combination ofcurcumin and oxaliplatin on human colon cancer cells in vitro and in vivo were investigatedwith colon cancer cells LoVo and colon cancer-bearing nude mice models through flowcytometry, transmission electron microscopy (TEM), reverse transcription-polymerase chainreaction (RT-PCR), western blotting, immunohistochemistry and immunofluorescencemethods. The main results as follow:
1. Curcumin could inhibit the growth of the tumor cells of different tissue origin (LoVo,SW480, MCF-7, BGC-823and SMMC-7721), has a dose-and time-dependent relationship;the growth of inhibition is more obvious in LoVo and MCF-7cells, while in normal cellsHK-2more than48h, when doses of more than20μg/mL, its growth has a certain inhibition.Suggesting that curcumin inhibition of cell growth may have tissue-specific, may not have asignificant tumor cell-specific.
2. Curcumin could significantly inhibit the growth and proliferation in LoVo cells, has abetter concentration-and time-dependent relationship; The inhibitory concentration50% (IC50) of curcumin were12.70±0.06,8.80±0.50and4.97±0.71μg/mL in LoVo cells at24,48and72h. Curcumin could make LoVo cell morphological changes, showing the typicalcharacteristics of apoptotic cells; arrest cell cycle at S phase, and induce apoptosis of LoVocells.
3. Curcumin can significantly reduce mitochondrial membrane potential, prompting therelease of cytochrome c, inhibition the expression of Bcl-2, Bcl-xL, c-myc and survivinprotein, up-regulation the expression of Bax, caspase-3and p53protein, increase the activityof caspase-9in LoVo cells, and induced apoptosis of LoVo cells through the mitochondrialpathway.
4. Combination of curcumin and oxaliplatin could synergistically inhibit proliferation ofLoVo cells, make the LoVo cells obvious morphological changes, arrest cell cycle at S phase,induce a large number of tumor cells death.
5. Combination of curcumin and oxaliplatin could synergistically reduce significantlymitochondrial membrane potential, activate the expression of caspase-3and caspase-9, inhibitthe expression of Bcl-2and Bcl-xL and promote the expression of Bax at the mRNA level,down-regulation the expression of Bcl-2, c-myc, and survivin protein, and promote theexpression of Bax and caspase-3at the protein level.
6.50mg/kg dose of curcumin can inhibit the growth of LoVo colonic xenografts in nudemice, and combination of curcumin and oxaliplatin group treatment could emerge additiveeffect on the inhibition of tumor growth, tumor inhibition rates were59.47%and70.56%,respectively. Curcumin group and combination of curcumin and oxaliplatin group treatmentdid not influence nude mice blood system, liver and kidney organs. Combination of curcuminand oxaliplatin group treatment could interfere with cell cycle arrest at S phase, inducingtumor cells apoptosis and necrosis. Using RT-PCR, western blotting andimmunohistochemistry to clarify the combination of curcumin and oxaliplatin treatment cansignificantly inhibit the Bcl-xL, Bcl-2, c-myc and survivin expression, promote the expressionof Bax, down-regulation the expression of HSP70protein, and activated caspase-3and PARPexpression in tumor tissue of tumor-bearing nude mice.
7. Curcumin could regulate the antioxidant system of colon cancer-bearing nude mice.Experiments in vivo showed that curcumin group and combination of curcumin andoxaliplatin group treatment could increase the levels of serum T-SOD and T-AOC, butdecrease the MDA level in tumor-bearing nude mice. They also improved the T-SOD, T-AOCand GR levels in liver and kidney of tumor-bearing nude mice, Furthermore, curcumin groupand combination of curcumin and oxaliplatin group treatment could increase the T-AOC level in spleen tissues, but not influence the T-SOD level in spleen, the GR level of spleen tissuewas the highest in curcumin group. To tumor tissues, curcumin group and combination ofcurcumin and oxaliplatin group treatment decreased T-AOC, T-SOD and GR levels. Besidesthat, the serum LDH level of tumor-bearing nude mice was suppressed by the treatment ofcurcumin group and combination of curcumin and oxaliplatin group. Curcumin grouptreatment could not influence the level of serum AKP, but combination of curcumin andoxaliplatin group treatment could increase the level of serum AKP significantly. Experimentsin vitro further showed that curcumin had strong effects on scavenging·OH radical, O2·-radical and DPPH radical.
In summary, curcumin could inhibit LoVo cells growth, induce LoVo cells arrest andapoptosis, Curcumin combination with oxaliplatin had a synergistic inhibitory effect on thegrowth of LoVo cells. Combination of curcumin and oxaliplatin used in the treatment of coloncancer, not only mitigated the toxicity of oxaliplatin, but also increased of anti-cancer effects,and did not find toxicity overlap of the two drugs. This suggested that the combination ofcurcumin and oxaliplatin treatment for colon cancer is feasible and worth of clinicalapplication.
引文
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