利尿酸和柳氮磺吡啶与Ang Ⅱ阻滞抗肿瘤机制的研究
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摘要
以激素非依赖性PC-3、激素依赖性LNCaP及胶质瘤C6细胞为研究对象,检测利尿酸(EA)与柳氮磺吡啶(SAS)、血管紧张素转换酶抑制剂(ACEI)、血管紧张素II受体拮抗剂(ARB)及联合用药对细胞存活率的影响,观察细胞增殖的抑制作用。通过检测LDH,GSH水平的变化;免疫组化方法观察前列腺组织AT1和VEGF的表达;RT-PCR检测CDK6、CyD1和P21、P27的表达;Western Blotting检测Bcl-2、Bax、P38、P65/P50、COX-2的蛋白表达,研究探讨其抗肿瘤的作用机制。
本实验结果显示EA和SAS抑制PC-3细胞的增殖,EA和SAS单独及联合应用均能耗竭细胞内GSH。二者诱导细胞死亡可能是通过P38和NF-κB途径下调CyD1、CDK6,上调p21、p27基因的转录来实现的。EA和或ACEI和ARB(坎地沙坦)抑制PC-3、LNCaP及C6细胞的增殖,表明EA、ACEI和坎地沙坦的作用与细胞激素依赖性的关系不大。单独应用ACEI和坎地沙坦并不影响细胞内GSH的含量。EA分别和ACEI及坎地沙坦联合应用抑制PC-3细胞增殖的机制与EA和SAS不同,主要是通过P38途径调控细胞周期相关蛋白的表达而发挥其抑制作用。
前列腺组织标本免疫组化染色证明腺上皮来源癌细胞不表达AT1、VEGF;通过对比观察EA和坎地沙坦对分别表达和不表达AT1、AT2的C6细胞和PC-3细胞的作用,发现坎地沙坦能抑制C6和PC-3细胞的增殖;坎地沙坦和EA共同作用于C6和PC-3细胞,Bax和P38蛋白表达增加,只有PC-3细胞P65蛋白表达下降。因此,本文认为坎地沙坦抑制细胞增殖可能与前列腺癌细胞AT1和AT2的表达无关,而是通过其他途径诱导细胞死亡的。
综上所述,本实验结果表明EA和SAS、EA和ACEI/ABR对肿瘤细胞抑制作用机制不同,能否改变细胞内GSH可能是其主要原因之一。
The prostate cancer is a serious disease of male reproductive system. The morbility of the prostate cancer is relatively low in china, but it is raising more and more consciousness recently. Radical surgery is the main method of curing the early stage prostate cancer, however, most patients can not be cured due to delayed diagnosis. The androgen withdraw can diminish the tumor size and down-regulate the level of prostate specific antigen (PSA), but can’t prevent the conversion from hormone sensitive-prostate cancer to hormone refractory prostate cancer. There is no effective therapy for the hormone refractory prostate cancer.
In many types of human tumor tissues, the intracellular GSH level can primarily or secondarily increased, and it is associated with the drugs resistance of tumor cells to the aldyl agents, adriamycin and platinum. EA is an electrophilic loop diuretics, it can bind with GSH, and decrease the intracellular GSH and it can also inhibite GSTs activity. The studies in vitro and in vivo have suggested that the decrease of intracellular GSH can prevent the drug resistance of chemotheropeutics.Sulfasalazine (SAS) can inhibite cystine uptake of Xc- of tumor cell, then decrease the synthesis of GSH, exhausts GSH, and results in the apoptosis.
Angiotension can promote the proliferation of both normal and tumor cells. In some studies, angiotensin(Ang II) can promote the tumor cell proliferation and angiogenesis and can also inhibit the tumor cell differentiation Studies in vitro and in vivo have shown that ACE inhibitor (ACEI) angiotensin II receptor block (ARB)can inhibit the growth of tumor cell. But, whether it can reach to the effective dosage and their side effect need to discuss.
In this study, Androgen dependent and indendent prostatic cancer cell was exposed to EA, SAS, captopril, lisinopril and candesartan, the proliferation rate of cell and tumor related gene and proteins was determined, the mechanisms of drug-induced proliferation inhibition of cells was discussed.
Methods:
Immunohistochemical staining was used to detect AT1 and VEGF expression in normal prostate, benign prostatic hyperplasia and prostatic cancer tissues. Prostatic cancer cell PC-3 (androgen dependent), LNCaP (androgen indendent) and glioma C6 was exposed to EA, SAS, captopril, lisinopril and candesartan, then it was analyzed that the proliferation rate of cell, the level of LDH and GSH. CDK6, CyD1, p21 and p27 mRNA expression was determined with RT-PCR method, Bcl-2, Bax, p38, p65, p50 and COX-2 exprission was detected using Western blotting analysis.
Results:
The cell viability and GSH level decreased, LDH release rate increased after exposure to EA or SAS, and coadministration of EA plus SAS resulted in the significan change of cell viability, GSH level and LDH release rate. EA or SAS exposure or coadministration of them did not change COX-2 exprission. EA and EA plus SAS results in the decreased expression of CDK6 and CyD1 and the increased expression of p21, p27 and p38, but SAS only inhibited CDK6 expression. p65 decreased and p50 did not change in tumor cells treated with EA, SAS alone or both drugs.The cell viability decreased after PC-3, LNCaP, C6 cells exposed to candesartan, captopril, lisinopril alone or plus EA. EA promoted LDH release and GSH exhaust, and candesartan, captopril, lisinopril intensified the LDH release of tumor cells induced by EA, but had no effect on the GSH exhaust. candesartan, captopril, lisinopril alone or coadministered with EA resulted in the downregulation of CDK6 and Bcl-2 of tumor cells. Increased p21, p38, bax and decreased p65 expression was found in PC-3 cells treated with EA plus candesartan. AT1 and AT2 expressed in C6 cells but not in PC-3 cells, and there was no distribution of angiotensinogen and ACE in both kinds of cells. EA upregulated AT1 and AT2 expression and downregulated Bcl-2 expression in C6 cells, candesartan intensified the AT2 but not AT1 expression. The results of immunohistochemical staining showed that AT1 and VEGF only expressed in the stroma but not in glandular epithelium of normal prostate, BPH and prostatic cancer tissues.
Discussion:
This study proven that cell death induced by EA and SAS is involved in the downregulation of cyclinD1 and CDK6, upregulation of p21 and p27 mediated by p38 and NF-κB but not COX-2.Proliferation inhibition of PC-3, LNCaP and C6 exposed to EA, ACEI and candesartan indicates that cell death is not related with the androgen dependent growth. GSH level is constant when cells exposed to candesartan, captopril, lisinopril alone, compared with the results of coadministration of EA and SAS, this indicates that proliferation inhibition or death of PC-3 cells is mainly involved in the expression of cyclin controlled by p38 signal pathway. Candesartan inhibite the proliferation of C6 and PC-3 cells with AT1 and AT2 and without respectively, bax and p38 increase and p65decrease in C6 and PC-3 cells after it exposed to candesartan. And all of these indicate that proliferation inhibition of tumor cells induced by candesartan is not mediated by AT1 or AT2.
According to above, this study investigats that EA and SAS、EA and ACEI/ABR exert inhibiting mechanisms on tumor cells, which whether change intracellular GSH or not is possibly one of the main causes. It can be concluded that p38MAPK signal pathway is strongly involved in the proliferation inhibition of prostatic cancer cells when compared with NF-κB signal pathway.
本实验结果显示EA和SAS抑制PC-3细胞的增殖,EA和SAS单独及联合应用均能耗竭细胞内GSH。二者诱导细胞死亡可能是通过P38和NF-κB途径下调CyD1、CDK6,上调p21、p27基因的转录来实现的。EA和或ACEI和ARB(坎地沙坦)抑制PC-3、LNCaP及C6细胞的增殖,表明EA、ACEI和坎地沙坦的作用与细胞激素依赖性的关系不大。单独应用ACEI和坎地沙坦并不影响细胞内GSH的含量。EA分别和ACEI及坎地沙坦联合应用抑制PC-3细胞增殖的机制与EA和SAS不同,主要是通过P38途径调控细胞周期相关蛋白的表达而发挥其抑制作用。
前列腺组织标本免疫组化染色证明腺上皮来源癌细胞不表达AT1、VEGF;通过对比观察EA和坎地沙坦对分别表达和不表达AT1、AT2的C6细胞和PC-3细胞的作用,发现坎地沙坦能抑制C6和PC-3细胞的增殖;坎地沙坦和EA共同作用于C6和PC-3细胞,Bax和P38蛋白表达增加,只有PC-3细胞P65蛋白表达下降。因此,本文认为坎地沙坦抑制细胞增殖可能与前列腺癌细胞AT1和AT2的表达无关,而是通过其他途径诱导细胞死亡的。
综上所述,本实验结果表明EA和SAS、EA和ACEI/ABR对肿瘤细胞抑制作用机制不同,能否改变细胞内GSH可能是其主要原因之一。
The prostate cancer is a serious disease of male reproductive system. The morbility of the prostate cancer is relatively low in china, but it is raising more and more consciousness recently. Radical surgery is the main method of curing the early stage prostate cancer, however, most patients can not be cured due to delayed diagnosis. The androgen withdraw can diminish the tumor size and down-regulate the level of prostate specific antigen (PSA), but can’t prevent the conversion from hormone sensitive-prostate cancer to hormone refractory prostate cancer. There is no effective therapy for the hormone refractory prostate cancer.
In many types of human tumor tissues, the intracellular GSH level can primarily or secondarily increased, and it is associated with the drugs resistance of tumor cells to the aldyl agents, adriamycin and platinum. EA is an electrophilic loop diuretics, it can bind with GSH, and decrease the intracellular GSH and it can also inhibite GSTs activity. The studies in vitro and in vivo have suggested that the decrease of intracellular GSH can prevent the drug resistance of chemotheropeutics.Sulfasalazine (SAS) can inhibite cystine uptake of Xc- of tumor cell, then decrease the synthesis of GSH, exhausts GSH, and results in the apoptosis.
Angiotension can promote the proliferation of both normal and tumor cells. In some studies, angiotensin(Ang II) can promote the tumor cell proliferation and angiogenesis and can also inhibit the tumor cell differentiation Studies in vitro and in vivo have shown that ACE inhibitor (ACEI) angiotensin II receptor block (ARB)can inhibit the growth of tumor cell. But, whether it can reach to the effective dosage and their side effect need to discuss.
In this study, Androgen dependent and indendent prostatic cancer cell was exposed to EA, SAS, captopril, lisinopril and candesartan, the proliferation rate of cell and tumor related gene and proteins was determined, the mechanisms of drug-induced proliferation inhibition of cells was discussed.
Methods:
Immunohistochemical staining was used to detect AT1 and VEGF expression in normal prostate, benign prostatic hyperplasia and prostatic cancer tissues. Prostatic cancer cell PC-3 (androgen dependent), LNCaP (androgen indendent) and glioma C6 was exposed to EA, SAS, captopril, lisinopril and candesartan, then it was analyzed that the proliferation rate of cell, the level of LDH and GSH. CDK6, CyD1, p21 and p27 mRNA expression was determined with RT-PCR method, Bcl-2, Bax, p38, p65, p50 and COX-2 exprission was detected using Western blotting analysis.
Results:
The cell viability and GSH level decreased, LDH release rate increased after exposure to EA or SAS, and coadministration of EA plus SAS resulted in the significan change of cell viability, GSH level and LDH release rate. EA or SAS exposure or coadministration of them did not change COX-2 exprission. EA and EA plus SAS results in the decreased expression of CDK6 and CyD1 and the increased expression of p21, p27 and p38, but SAS only inhibited CDK6 expression. p65 decreased and p50 did not change in tumor cells treated with EA, SAS alone or both drugs.The cell viability decreased after PC-3, LNCaP, C6 cells exposed to candesartan, captopril, lisinopril alone or plus EA. EA promoted LDH release and GSH exhaust, and candesartan, captopril, lisinopril intensified the LDH release of tumor cells induced by EA, but had no effect on the GSH exhaust. candesartan, captopril, lisinopril alone or coadministered with EA resulted in the downregulation of CDK6 and Bcl-2 of tumor cells. Increased p21, p38, bax and decreased p65 expression was found in PC-3 cells treated with EA plus candesartan. AT1 and AT2 expressed in C6 cells but not in PC-3 cells, and there was no distribution of angiotensinogen and ACE in both kinds of cells. EA upregulated AT1 and AT2 expression and downregulated Bcl-2 expression in C6 cells, candesartan intensified the AT2 but not AT1 expression. The results of immunohistochemical staining showed that AT1 and VEGF only expressed in the stroma but not in glandular epithelium of normal prostate, BPH and prostatic cancer tissues.
Discussion:
This study proven that cell death induced by EA and SAS is involved in the downregulation of cyclinD1 and CDK6, upregulation of p21 and p27 mediated by p38 and NF-κB but not COX-2.Proliferation inhibition of PC-3, LNCaP and C6 exposed to EA, ACEI and candesartan indicates that cell death is not related with the androgen dependent growth. GSH level is constant when cells exposed to candesartan, captopril, lisinopril alone, compared with the results of coadministration of EA and SAS, this indicates that proliferation inhibition or death of PC-3 cells is mainly involved in the expression of cyclin controlled by p38 signal pathway. Candesartan inhibite the proliferation of C6 and PC-3 cells with AT1 and AT2 and without respectively, bax and p38 increase and p65decrease in C6 and PC-3 cells after it exposed to candesartan. And all of these indicate that proliferation inhibition of tumor cells induced by candesartan is not mediated by AT1 or AT2.
According to above, this study investigats that EA and SAS、EA and ACEI/ABR exert inhibiting mechanisms on tumor cells, which whether change intracellular GSH or not is possibly one of the main causes. It can be concluded that p38MAPK signal pathway is strongly involved in the proliferation inhibition of prostatic cancer cells when compared with NF-κB signal pathway.
引文
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