羧胺三唑的抗癌新机制抑制肿瘤相关巨噬细胞中促炎细胞因子的释放
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摘要
研究背景
羧胺三唑(carboxyamidotriazole, CAI)是一种非细胞毒类药物,能够抑制体外多种肿瘤细胞系的增殖,诱导肿瘤细胞凋亡。CAI还被认为能够抑制血管的形成和抑制肿瘤的转移。这些作用被推测可能与CAI抑制钙离子跨膜内流有关,但其具体的分子机制尚无定论。
我们实验室近年来发现,CAI不仅对肿瘤细胞有直接作用,还在一系列急慢性炎症模型中表现出良好的抗炎作用。我们通过巴豆油致小鼠耳肿胀模型、棉球植入致大鼠肉芽肿实验模型和大鼠佐剂性关节炎模型分别观察到CAI对急性炎症、慢性增殖相和自身免疫性炎症均有明显的抑制作用,并且能明显下调炎症部位或炎症动物血浆中促炎细胞因子的含量。
炎症和癌症之间有着重要的关系。早在19世纪,Virchow提出了慢性炎症可能会导致细胞增殖从而产生肿瘤的假说。进入21世纪以来,炎癌关系重新引起了科学家们极大的兴趣。流行病学研究结果表明感染和慢性炎症与肿瘤的发生有很大的关联。另有很多研究证实,在肿瘤出现后的生长过程中,肿瘤微环境中的炎症细胞和介质也会扮演肿瘤细胞“帮凶”的角色,其中肿瘤相关巨噬细胞(TAMs)和肿瘤坏死因子-α(TNF-α)等促炎细胞因子的作用得到广泛认同。
综合以上背景,我们提出了以下设想：具有抗癌和抗炎双重作用的CAI是否能够作用于在炎、癌发展中均发挥重要作用的巨噬细胞?除能抑制炎症模型中促炎细胞因子,是否还能抑制肿瘤微环境中促炎细胞因子的产生?CAI抑制肿瘤微环境中的促炎细胞因子是否是其抗肿瘤作用的另一个机制?在本项课题,我们围绕这些问题展开了研究。
研究方法
我们提取佐剂性关节炎大鼠的腹腔巨噬细胞(动物连续21天给予溶剂或20mg/kg/d CAI),进行酶联免疫吸附试验(ELISA)测定其TNF-α的分泌。建立C57BL/6小鼠Lewis肺癌(LLC)模型,动物连续14天给予溶剂或20mg/kg/d CAI,对其肿瘤组织中的TNF-α进行免疫组化染色,用ELISA方法测定其肿瘤组织匀浆中TNF-α的含量,并获取肿瘤组织中的巨噬细胞,进行逆转录-聚合酶链式反应试验(RT-PCR)测定其中TNF-αmRNA的表达。另外,我们参考文献,将原代培养的小鼠腹腔巨噬细胞或小鼠巨噬细胞系RAW264.7细胞用Lewis肺癌细胞(LLC细胞)的条件培养基进行诱导,或将这些巨噬细胞直接与LLC细胞共培养,用RT-PCR方法和ELISA方法检测药物对这些经肿瘤条件诱导的巨噬细胞合成和释放TNF-α的影响。在这些实验中,我们采用影响多种细胞因子的药物——地塞米松(Dexamethasone, DEX)作为工具,研究了DEX对TNF-α的影响及其对CAI效应的增强作用。
我们在巨噬细胞与LLC细胞共培养的体系中,用CCK-8试剂测定腹腔巨噬细胞对LLC细胞增殖的促进作用,并观察DEX增强共培养体系中CAI对LLC细胞增殖的抑制作用；通过结晶紫染色方法观察药物预处理的RAW264.7巨噬细胞对LLC细胞迁移和侵袭的影响,并在该体系中加入TNF-α抗体观察TNF-α在巨噬细胞影响LLC细胞迁移过程中的作用。
我们用CCK-8试剂还观察了在单独培养LLC细胞时,DEX对CAI抑制LLC细胞增殖作用的影响；并在小鼠LLC模型中,观察了DEX对CAI抑制肿瘤生长作用的影响,对肿瘤组织冰冻切片进行CD31分子的免疫组化染色,观察血管生长的情况。
为验证DEX对CAI抗肿瘤效应的增强较具有普遍性,我们利用A549裸鼠移植瘤模型对二者联合用药的效应再次进行了研究,并检测了血管生长的情况、肿瘤组织匀浆中TNF-α含量的变化和联合用药对荷瘤动物腹腔巨噬细胞中TNF-α释放的影响。
研究结果
CAI对佐剂性关节炎大鼠腹腔巨噬细胞中炎症介质TNF-α的释放有显著的抑制作用。不仅如此,肿瘤组织免疫组化染色、ELISA和荧光定量PCR实验结果显示,它也能明显抑制LLC肿瘤组织巨噬细胞中TNF-α的表达和释放。对肿瘤组织内的CD31分子进行染色发现,CAI对LLC肿瘤组织中血管的形成有抑制作用。
体外实验中,我们发现正常C57BL/6小鼠的腹腔巨噬细胞在与LLC肿瘤细胞共培养时,p65向细胞核处聚集,可能表示有炎症反应在一定程度上被激活。CAI能够显著抑制与LLC肿瘤细胞共培养后的小鼠腹腔巨噬细胞TNF-α释放的增加,对经LLC肿瘤条件培养基诱导的小鼠腹腔巨噬细胞IL-10生成有上调作用。不仅如此,CAI还能显著抑制受LLC肿瘤细胞条件培养基诱导后的小鼠巨噬细胞样细胞RAW264.7中TNF-α、IL-6表达和释放的增加。
在体外共培养模型中,我们发现正常C57BL/6小鼠的腹腔巨噬细胞能够显著刺激同源的LLC肿瘤细胞的增殖,而DEX和CAI能够有效抑制腹腔巨噬细胞的这种作用。RAW264.7细胞显著促进LLC肿瘤细胞的迁移和侵袭,在这个体系中加入TNF-α抗体能够有效抑制RAW264.7细胞引起的LLC细胞迁移,经过CAI和/或DEX预处理的RAW264.7细胞促进LLC细胞迁移和侵袭的作用减弱。
CAI能够直接作用于LLC肿瘤细胞,显著抑制其增殖,而DEX未能促进CAI对LLC肿瘤细胞的直接抑制作用。CAI与DEX联合用药显著抑制C57BL/6小鼠中LLC肿瘤的生长,延长荷瘤动物的生存期,并且对动物的体重和生存状态没有产生明显影响。
在裸鼠A549移植瘤模型中,CAI与DEX联合用药能够显著抑制A549移植瘤的生长,显著减少A549抑制瘤组织中血管的生成和下调A549抑制瘤组织匀浆TNF-α和TGF-β的含量。通过对荷瘤动物腹腔巨噬细胞进行研究,发现CAI和DEX联合用药将腹腔巨噬细胞中TNF-α的释放降至极低水平。
研究结论
CAI不仅对肿瘤细胞有直接作用,影响炎症模型中的细胞因子从而发挥抗炎作用,还能够对肿瘤环境中巨噬细胞合成或释放细胞因子产生影响,这些细胞包括体外经肿瘤条件诱导的巨噬细胞和体内移植瘤组织内的巨噬细胞。在这些模型中,能够广泛影响细胞因子的药物——DEX也能够在一定程度上抑制肿瘤的生长,并对CAI的抗肿瘤效应有着很强的促进作用。因此,影响肿瘤微环境中细胞因子的产生可能是CAI抗肿瘤作用的机制之一。总结我们在炎症模型和肿瘤模型中发现的CAI对炎症介质的影响,我们认为CAI成为研究炎癌关系非常良好的工具药物。小剂量地塞米松与CAI的联合应用在肿瘤发展的增殖、迁移、侵袭和血管生长等环节都表现出很强的抑制作用,对于优化CAI的抗肿瘤作用有着重要意义,将来可能能够成为临床上理想的联合用药方案之一。
Backgound
Carboxyamidotriazole (CAI) is a non-cytotoxic anticancer drug in development. It inhibits proliferation and induces apoptosis of some cancer cells. A series of clinical trails have shown that the adverse effects of the drug are slight comparing with other anticancer drugs, although its effect is still in investigation. It has been suggested that CAI is a voltage-independent calcium channel inhibitor of cancer cells, but the exact anti-cancer mechanism is not quite clear yet.
In our previous study, we found that CAI also possessed great anti-inflammation action in a variety of animal models of acute and chronic inflammation. In the adjuvant-induced arthritis (AA) model, the decrease of the pro-inflammatory cytokines at the site of inflammation and in serums by CAI was observed.
Considering CAI has both anti-cancer and anti-inflammation activities, we then focused on its effects on macrophages, which were important both for tumor growth and inflammation processes. We wondered if CAI might also have effects on the pro-inflammatory cytokines production in tumor associated macrophages (TAMs), which might be one of the mechanisms for the anti-cancer actions of CAI.
Methods
Adjuvant-Induced Arthritis (AA) Model was established and peritoneal macrophages were isolated from AA rats on day 21. Tumor necrosis factor-a (TNF-α) production in these macrophages was measured by ELISA assay. Lewis Lung Carcinoma (LLC) Model was established and the tumor tissues were obtained on day 14. TNF-αand CD31 in the tumor tissues was stained immunohistochemically and the concentration of TNF-a was measured by ELISA assay. The macrophages were isolated from the tumor tissues with collagenase and TNF-a mRNA level in these macrophages was determined by RT-PCR assay. The peritoneal macrophages from C57 mice or RAW264.7 macrophages were co-cultured with LLC cells or LLC conditioned medium. The TNF-a and Interleukin-6 (IL-6) expression in these macrophages was tested by ELISA and RT-PCR assay. In the above tests, dexamethasone (DEX) was combined with CAI as it is known to inhibit the pro-inflammatory cytokines.
The proliferation of the LLC cells cultured alone or with macrophages was measured with CCK-8 agent. The migration and invasion of the LLC cells cultured alone or with macrophages was measured with crystal violet agent. The TNF-a neutralizing antibody was used to verify the action of TNF-a.
A549 xenograft model in nude mice was established to see whether the great inhibition caused by the combination of CAI and DEX was a much commen effect. The blood vessel growth and TNF-a concentration in tumor tissues were also tested.
Results
CAI suppressed TNF-a production in peritoneal macrophages isolated from rats of adjuvant-induced arthritis.
CAI decreased TNF-a in LLC tumor tissues and suppressed the expression of mRNA for TNF-a in tumor tissue macrophages. It also inhibited the angiogenesis in LLC tumor tissues.
CAI inhibited TNF-a and IL-6 production in macrophages induced by LLC cells or its conditioned medium. Proliferation of LLC cells was promoted by peritoneal macrophages; DEX enhanced the inhibition of CAI on the proliferation of LLC cells co-cultured with peritoneal macrophages instead of LLC cells cultured alone. RAW264.7 cells promoted LLC cells invasion and the activity was inhibited if RAW264.7 cells were pre-treated with CAI. The activity was also inhibited if the TNF-a neutralizing antibody was added in the co-culture system.
DEX did not affect the direct inhibition of CAI on the proliferation of LLC cells cultured alone. But the combination treatment of CAI and DEX significantly inhibited the LLC tumor growth in mice with the survival time prolonged. The addition of DEX did not influence the body weights.
In the A549 xenograft model, it is also observed that combination of CAI and DEX significantly inhibited the tumor growth and blood vessels growth in the tumor tissues. The concentrations of TNF-αand TGF-βin tumor homogenates and TNF-αproduction in peritoneal macrophages of A549 tumor bearing mice were all decreased by CAI and/or DEX.
Conclusion
In summary, we have found that CAI can not only act on tumor cells directly, but also on macrophages, including those in arthritis model and TAMs. It can suppress TNF-a and IL-6 production, break the "smoldering" inflammation balance in TAMs, and thus inhibit tumor growth indirectly. The findings suggest that CAI exerts anti-cancer activities may be due to its direct actions on both tumor cells and TAMs. The newly found anti-inflammation activity may make CAI one of effective tools to study the relationship between inflammation and cancer, and the combination with low dose DEX may be of great importance for clinical application of CAI.
羧胺三唑(carboxyamidotriazole, CAI)是一种非细胞毒类药物,能够抑制体外多种肿瘤细胞系的增殖,诱导肿瘤细胞凋亡。CAI还被认为能够抑制血管的形成和抑制肿瘤的转移。这些作用被推测可能与CAI抑制钙离子跨膜内流有关,但其具体的分子机制尚无定论。
我们实验室近年来发现,CAI不仅对肿瘤细胞有直接作用,还在一系列急慢性炎症模型中表现出良好的抗炎作用。我们通过巴豆油致小鼠耳肿胀模型、棉球植入致大鼠肉芽肿实验模型和大鼠佐剂性关节炎模型分别观察到CAI对急性炎症、慢性增殖相和自身免疫性炎症均有明显的抑制作用,并且能明显下调炎症部位或炎症动物血浆中促炎细胞因子的含量。
炎症和癌症之间有着重要的关系。早在19世纪,Virchow提出了慢性炎症可能会导致细胞增殖从而产生肿瘤的假说。进入21世纪以来,炎癌关系重新引起了科学家们极大的兴趣。流行病学研究结果表明感染和慢性炎症与肿瘤的发生有很大的关联。另有很多研究证实,在肿瘤出现后的生长过程中,肿瘤微环境中的炎症细胞和介质也会扮演肿瘤细胞“帮凶”的角色,其中肿瘤相关巨噬细胞(TAMs)和肿瘤坏死因子-α(TNF-α)等促炎细胞因子的作用得到广泛认同。
综合以上背景,我们提出了以下设想：具有抗癌和抗炎双重作用的CAI是否能够作用于在炎、癌发展中均发挥重要作用的巨噬细胞?除能抑制炎症模型中促炎细胞因子,是否还能抑制肿瘤微环境中促炎细胞因子的产生?CAI抑制肿瘤微环境中的促炎细胞因子是否是其抗肿瘤作用的另一个机制?在本项课题,我们围绕这些问题展开了研究。
研究方法
我们提取佐剂性关节炎大鼠的腹腔巨噬细胞(动物连续21天给予溶剂或20mg/kg/d CAI),进行酶联免疫吸附试验(ELISA)测定其TNF-α的分泌。建立C57BL/6小鼠Lewis肺癌(LLC)模型,动物连续14天给予溶剂或20mg/kg/d CAI,对其肿瘤组织中的TNF-α进行免疫组化染色,用ELISA方法测定其肿瘤组织匀浆中TNF-α的含量,并获取肿瘤组织中的巨噬细胞,进行逆转录-聚合酶链式反应试验(RT-PCR)测定其中TNF-αmRNA的表达。另外,我们参考文献,将原代培养的小鼠腹腔巨噬细胞或小鼠巨噬细胞系RAW264.7细胞用Lewis肺癌细胞(LLC细胞)的条件培养基进行诱导,或将这些巨噬细胞直接与LLC细胞共培养,用RT-PCR方法和ELISA方法检测药物对这些经肿瘤条件诱导的巨噬细胞合成和释放TNF-α的影响。在这些实验中,我们采用影响多种细胞因子的药物——地塞米松(Dexamethasone, DEX)作为工具,研究了DEX对TNF-α的影响及其对CAI效应的增强作用。
我们在巨噬细胞与LLC细胞共培养的体系中,用CCK-8试剂测定腹腔巨噬细胞对LLC细胞增殖的促进作用,并观察DEX增强共培养体系中CAI对LLC细胞增殖的抑制作用；通过结晶紫染色方法观察药物预处理的RAW264.7巨噬细胞对LLC细胞迁移和侵袭的影响,并在该体系中加入TNF-α抗体观察TNF-α在巨噬细胞影响LLC细胞迁移过程中的作用。
我们用CCK-8试剂还观察了在单独培养LLC细胞时,DEX对CAI抑制LLC细胞增殖作用的影响；并在小鼠LLC模型中,观察了DEX对CAI抑制肿瘤生长作用的影响,对肿瘤组织冰冻切片进行CD31分子的免疫组化染色,观察血管生长的情况。
为验证DEX对CAI抗肿瘤效应的增强较具有普遍性,我们利用A549裸鼠移植瘤模型对二者联合用药的效应再次进行了研究,并检测了血管生长的情况、肿瘤组织匀浆中TNF-α含量的变化和联合用药对荷瘤动物腹腔巨噬细胞中TNF-α释放的影响。
研究结果
CAI对佐剂性关节炎大鼠腹腔巨噬细胞中炎症介质TNF-α的释放有显著的抑制作用。不仅如此,肿瘤组织免疫组化染色、ELISA和荧光定量PCR实验结果显示,它也能明显抑制LLC肿瘤组织巨噬细胞中TNF-α的表达和释放。对肿瘤组织内的CD31分子进行染色发现,CAI对LLC肿瘤组织中血管的形成有抑制作用。
体外实验中,我们发现正常C57BL/6小鼠的腹腔巨噬细胞在与LLC肿瘤细胞共培养时,p65向细胞核处聚集,可能表示有炎症反应在一定程度上被激活。CAI能够显著抑制与LLC肿瘤细胞共培养后的小鼠腹腔巨噬细胞TNF-α释放的增加,对经LLC肿瘤条件培养基诱导的小鼠腹腔巨噬细胞IL-10生成有上调作用。不仅如此,CAI还能显著抑制受LLC肿瘤细胞条件培养基诱导后的小鼠巨噬细胞样细胞RAW264.7中TNF-α、IL-6表达和释放的增加。
在体外共培养模型中,我们发现正常C57BL/6小鼠的腹腔巨噬细胞能够显著刺激同源的LLC肿瘤细胞的增殖,而DEX和CAI能够有效抑制腹腔巨噬细胞的这种作用。RAW264.7细胞显著促进LLC肿瘤细胞的迁移和侵袭,在这个体系中加入TNF-α抗体能够有效抑制RAW264.7细胞引起的LLC细胞迁移,经过CAI和/或DEX预处理的RAW264.7细胞促进LLC细胞迁移和侵袭的作用减弱。
CAI能够直接作用于LLC肿瘤细胞,显著抑制其增殖,而DEX未能促进CAI对LLC肿瘤细胞的直接抑制作用。CAI与DEX联合用药显著抑制C57BL/6小鼠中LLC肿瘤的生长,延长荷瘤动物的生存期,并且对动物的体重和生存状态没有产生明显影响。
在裸鼠A549移植瘤模型中,CAI与DEX联合用药能够显著抑制A549移植瘤的生长,显著减少A549抑制瘤组织中血管的生成和下调A549抑制瘤组织匀浆TNF-α和TGF-β的含量。通过对荷瘤动物腹腔巨噬细胞进行研究,发现CAI和DEX联合用药将腹腔巨噬细胞中TNF-α的释放降至极低水平。
研究结论
CAI不仅对肿瘤细胞有直接作用,影响炎症模型中的细胞因子从而发挥抗炎作用,还能够对肿瘤环境中巨噬细胞合成或释放细胞因子产生影响,这些细胞包括体外经肿瘤条件诱导的巨噬细胞和体内移植瘤组织内的巨噬细胞。在这些模型中,能够广泛影响细胞因子的药物——DEX也能够在一定程度上抑制肿瘤的生长,并对CAI的抗肿瘤效应有着很强的促进作用。因此,影响肿瘤微环境中细胞因子的产生可能是CAI抗肿瘤作用的机制之一。总结我们在炎症模型和肿瘤模型中发现的CAI对炎症介质的影响,我们认为CAI成为研究炎癌关系非常良好的工具药物。小剂量地塞米松与CAI的联合应用在肿瘤发展的增殖、迁移、侵袭和血管生长等环节都表现出很强的抑制作用,对于优化CAI的抗肿瘤作用有着重要意义,将来可能能够成为临床上理想的联合用药方案之一。
Backgound
Carboxyamidotriazole (CAI) is a non-cytotoxic anticancer drug in development. It inhibits proliferation and induces apoptosis of some cancer cells. A series of clinical trails have shown that the adverse effects of the drug are slight comparing with other anticancer drugs, although its effect is still in investigation. It has been suggested that CAI is a voltage-independent calcium channel inhibitor of cancer cells, but the exact anti-cancer mechanism is not quite clear yet.
In our previous study, we found that CAI also possessed great anti-inflammation action in a variety of animal models of acute and chronic inflammation. In the adjuvant-induced arthritis (AA) model, the decrease of the pro-inflammatory cytokines at the site of inflammation and in serums by CAI was observed.
Considering CAI has both anti-cancer and anti-inflammation activities, we then focused on its effects on macrophages, which were important both for tumor growth and inflammation processes. We wondered if CAI might also have effects on the pro-inflammatory cytokines production in tumor associated macrophages (TAMs), which might be one of the mechanisms for the anti-cancer actions of CAI.
Methods
Adjuvant-Induced Arthritis (AA) Model was established and peritoneal macrophages were isolated from AA rats on day 21. Tumor necrosis factor-a (TNF-α) production in these macrophages was measured by ELISA assay. Lewis Lung Carcinoma (LLC) Model was established and the tumor tissues were obtained on day 14. TNF-αand CD31 in the tumor tissues was stained immunohistochemically and the concentration of TNF-a was measured by ELISA assay. The macrophages were isolated from the tumor tissues with collagenase and TNF-a mRNA level in these macrophages was determined by RT-PCR assay. The peritoneal macrophages from C57 mice or RAW264.7 macrophages were co-cultured with LLC cells or LLC conditioned medium. The TNF-a and Interleukin-6 (IL-6) expression in these macrophages was tested by ELISA and RT-PCR assay. In the above tests, dexamethasone (DEX) was combined with CAI as it is known to inhibit the pro-inflammatory cytokines.
The proliferation of the LLC cells cultured alone or with macrophages was measured with CCK-8 agent. The migration and invasion of the LLC cells cultured alone or with macrophages was measured with crystal violet agent. The TNF-a neutralizing antibody was used to verify the action of TNF-a.
A549 xenograft model in nude mice was established to see whether the great inhibition caused by the combination of CAI and DEX was a much commen effect. The blood vessel growth and TNF-a concentration in tumor tissues were also tested.
Results
CAI suppressed TNF-a production in peritoneal macrophages isolated from rats of adjuvant-induced arthritis.
CAI decreased TNF-a in LLC tumor tissues and suppressed the expression of mRNA for TNF-a in tumor tissue macrophages. It also inhibited the angiogenesis in LLC tumor tissues.
CAI inhibited TNF-a and IL-6 production in macrophages induced by LLC cells or its conditioned medium. Proliferation of LLC cells was promoted by peritoneal macrophages; DEX enhanced the inhibition of CAI on the proliferation of LLC cells co-cultured with peritoneal macrophages instead of LLC cells cultured alone. RAW264.7 cells promoted LLC cells invasion and the activity was inhibited if RAW264.7 cells were pre-treated with CAI. The activity was also inhibited if the TNF-a neutralizing antibody was added in the co-culture system.
DEX did not affect the direct inhibition of CAI on the proliferation of LLC cells cultured alone. But the combination treatment of CAI and DEX significantly inhibited the LLC tumor growth in mice with the survival time prolonged. The addition of DEX did not influence the body weights.
In the A549 xenograft model, it is also observed that combination of CAI and DEX significantly inhibited the tumor growth and blood vessels growth in the tumor tissues. The concentrations of TNF-αand TGF-βin tumor homogenates and TNF-αproduction in peritoneal macrophages of A549 tumor bearing mice were all decreased by CAI and/or DEX.
Conclusion
In summary, we have found that CAI can not only act on tumor cells directly, but also on macrophages, including those in arthritis model and TAMs. It can suppress TNF-a and IL-6 production, break the "smoldering" inflammation balance in TAMs, and thus inhibit tumor growth indirectly. The findings suggest that CAI exerts anti-cancer activities may be due to its direct actions on both tumor cells and TAMs. The newly found anti-inflammation activity may make CAI one of effective tools to study the relationship between inflammation and cancer, and the combination with low dose DEX may be of great importance for clinical application of CAI.
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