大麻素Ⅱ型受体激动剂在恶性黑素瘤中血管生成作用机制的研究
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摘要
研究背景与目的
恶性黑素瘤(malignant melanoma,MM)是一种高度恶性的肿瘤,发生隐蔽,易发生血管和淋巴结转移,发展迅速、预后差、死亡率高。删的生长和转移依赖于肿瘤内的血管生成(angiogenesis),而血管内皮生长因子(vascularendothelial growth factor,VEGF)在肿瘤血管生成机制中处于核心地位。研究表明MM血管生成十分活跃,VEGF作为最重要的促血管生成因子而逐渐成为研究热点。
已知的大麻素受体(cannabinoid receptor CB-R)分为Ⅰ型大麻素受体(cannabinoid receptor 1,CB-R1)和Ⅱ型大麻素受体(cannabinoid receptor 2,CB-R2),均为G-蛋白偶联受体(G-protein coupled receptors,GPCRs),GPCRs在肿瘤的生长和血管生成中具有重要作用。研究表明CB-R2具有抗炎症、抗增殖、抗肿瘤等作用,CB-R2激动剂体外试验可诱导细胞凋亡,体内试验可抑制肿瘤的生长而无明显的副反应。本课题组前期研究发现,CB-R2受体在MM组织中呈高表达,但对其在删中是否参予迁移、侵袭和血管生成的作用机制尚不完全明确。如能证实CB-R2激动剂具有抗血管生成和抑制肿瘤生长的功能,其可能成为治疗MM新的抗血管生成靶点药物。本课题的目的是通过体外和体内实验模型,拟证明CB-R2参与MM的发病过程,探讨CB-R2受体激动剂JWH-133和WIN55,212-2在MM中的抗肿瘤活性和抗血管生成的作用与机制,为其在临床应用提供新思路。
研究方法
1.体外实验以人恶性黑素瘤A375细胞为研究模型
应用免疫荧光检测CB-R2在A375细胞中的表达与定位;RT-PCR和Westernblot检测CB-R2在A375细胞中mRNA和蛋白水平的表达;Real time PCR和免疫组化检测CB-R2激动剂JWH-133和WIN55,212-2对A375细胞CB-R2表达的影响;MTT、划痕实验和Transwell小室模型检测JWH-133和WIN55,212-2对A375细胞增殖、迁移和侵袭作用的影响;Real-time PCR、和ELISA检测JWH-133和WIN55,212-2对A375细胞VEGF在mRNA和蛋白水平表达的影响;TUNEL检测JWH-133和WIN55,212-2对A375细胞凋亡的影响。
2.体内实验以人恶性黑素瘤A375细胞裸鼠移植瘤为研究模型
建立人恶性黑素瘤裸鼠移植瘤动物模型,观察体内成瘤情况。应用免疫荧光检测瘤组织中CB-R2的表达与定位;Real-time PCR、western blot和免疫组化检测CB-R2激动剂JWH-133和win55,212-2对肿瘤组织中CB-R2和VEGF在mRNA和蛋白水平表达的影响;TUNEL检测JWH-133和win55,212-2对肿瘤组织细胞凋亡的影响。
结果
1.人恶性黑素瘤A375细胞体外模型实验结果
①人恶性黑素瘤A375细胞在mRNA和蛋白水平均表达CB-R2,其表达定位于胞浆和胞膜,胞核无染色。②不同浓度JWH-133和WIN55,212-2(0.01/0.1/1/10/100umol/L)对A375细胞增殖具有抑制作用,48h达到高峰(P＜0.05);而两种药物对A375细胞增殖的抑制作用,经统计学分析比较无明显差异(P＞0.05)。③JWH-133和WIN55,212-2抑制A375细胞的迁移和侵袭能力;与对照组比较,1umol/L浓度JWH-133组和WIN55,212-2组细胞相对迁移面积显著降低,差异具有统计学意义(P＜0.05);1umol/L浓度JWH-133组和WIN55,212-2组细胞穿膜细胞数与对照组比较明显减少,差异具有统计学意义(P＜0.05);而两种药物组的细胞相对迁移面积和穿膜细胞数,经统计学分析比较无明显差异(P＞0.05)。④不同浓度JWH-133和win55,212-2(1umol/5umol/10umol/L)刺激A375细胞24h,48h和72h后,可降低VEGF在不同时相点mRNA和蛋白水平的表达,与对照组比较差异具有统计学意义(P＜0.05);并且这种抑制效应呈时间剂量依赖关系,JWH-133和WIN55,212-2剂量越大,刺激时间越长,VEGF表达的降低越明显。⑤1umol/L浓度JWH-133和WIN55,212-2刺激A375细胞24h,48h和72h后,可诱导A375细胞凋亡,JWH-133组A375细胞凋亡率分别为7.22%、9.1 7%和11.45%;WIN5 5,212-2组A375细胞凋亡率分别为6.45%、8.12%和10.34%;而对照组凋亡率为6.35%、6.09%和6.39%,JWH-133组和WIN55,212-2组与对照组凋亡率比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。
2.人恶性黑素瘤A375细胞裸鼠移植瘤模型实验结果
①JWH-133和WIN55,212-2可以抑制人恶性黑素瘤裸鼠移植瘤的生长,抑瘤率分别为43.14%和39.47%。②予JWH-133和WIN55,212-2,肿瘤组织可在mRNA和蛋白水平上调CB-R2的表达,与对照组比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。③JWH-133和WIN55,212-2在mRNA和蛋白水平降低肿瘤组织中VEGF的表达;与对照组比较,差异具有统计学意义(P＜0.05);两种药物之间经统计学分析比较无明显差异(P＞0.05)。④JWH-133和WIN55,212-2可诱导肿瘤组织中肿瘤细胞凋亡,对照组、JWH-133组和WIN55,212-2组肿瘤组织凋亡率分别为7.33%、12.84%和11.57%。JWH-133组和WIN55,212-2组与对照组凋亡率比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。
结论
1.大麻素Ⅱ型受体CB-R2参与了MM的发病过程;
2.JWH-133和WIN55,212-2可以抑制A375细胞增殖、迁移和侵袭的能力;
3.体外和体内实验模型中,JWH-133和WIN55,212-2可诱导MM肿瘤细胞凋亡:
4.体外和体内实验模型中,JWH-133和WIN55,212-2可降低MM肿瘤细胞和组织VEGF的表达和分泌,抑制血管生成,控制肿瘤的生长;
5.JWH-133和WIN55,212-2在抑制恶性黑素瘤细胞增殖、迁移、侵袭能力以及促进细胞凋亡等作用机制方面,二者无显著差异。
Research Background and Objectives
Malignant melanoma(MM) causes the greatest number of worldwide skin cancers related to deaths.It may lead to rapid invasion and blood vessel and lymph metastasis.Proangiogenesis factor vascular endothelial growth factor(VEGF) is the core of angiogenesis mechanism.Researches have shown that MM angiogenesis is so active that tumor cells stimulate the proliferation,migration and tubulogensis of endothelial cells by producing large amount of VEGF and thus lead to angiogenesis of malignant tumor.Therefore,VEGF has been one of the frontiers in MM research in the mechanism of antiangiogenesis.
There are at least two types of cannabinoid receptor,cannabinoid receptor 1 (CB-R1) and cannabinoid receptor 2(CB-R2) both G- protein coupled receptors(GPCRs).GPCRs plays an important role in the development and angiogenesis of malignant tumors.Researches have shown that CB-R2 agonist have effect on apoptosis in vitro and inhibit the growth of tumor in vivo and downregulation expression in VEGF.Our previous studies have shown that CB-R2 has high significance expression in MM,but it is yet unknown whether CB-R2 contributes to migration,invasion and angiogenesis in MM.The study is to investigate the effect of CB-R2 agonist JWH-133 and WIN55,212-2 in human malignant melanoma cell line A375 and xenografted malignant melanoma in nude mice,trying to find whether they have the effect of antiangiogenesis by regulating the expression of VEGF.Thus,it is to provide the novel targets for the treatment of MM.
Methods
1.Study on human malignant melanoma cell line A375 in vitro
Firstly,we detect the expression and location of CB-R2 in A375 cell line by immunofluorescence,finding the effect of CB-R2 agonist JWH-133 and WIN55,212-2 on the expression of CB-R2 mRNA and protein levels by Real-time PCR,immunohistochemistry and Western blot.Then,we explore the inhibitory effect of CB-R2 agonist in antiproliferation,migration and invasion by MTT, wound-healing and Transwell chamber.Furthermore,we detecte the relationship between tumor cells growth and the production of angiogenic factors VEGF by ELISA and Real-time PCR.Finally,we study the effect on apoptosis of CB-R2 agonist by TUNEL.
2.Study on xenografting malignant melanoma nude mice model in vivo
Establish the xenografting malignant melanoma nude mice model to observe the growth of the tumor,detecting the expression and location of CB-R2 in tumor tissue by immunofluorescence.And then we study the effect of CB-R2 agonist JWH-133 and WIN55,212-2 on the expression of CB-R2 mRNA and protein in tumor tissue by Real-time PCR,immunohistochemistry and Western blot. Furhermore we detecte the relationship between tumor cells growth and the production of angiogenic factors VEGF by Western blot and Real-time PCR.Finally, we study the effect on apoptosis of CB-R2 agonist by TUNEL.
Results
1.in vitro:
(1)A375 cells have expressed the CB-R2 in mRNA and protein levels.The expression is located in kytoplasmand membrane,no dyeing on nucleus.
(2)JWH-133 and WIN55,212-2 have effect on the inhibition of A375 cells at different concentrations(0.01/0.1/1/10/100umol/L) with the peak time on 48h (p＜0.05).No significantly difference between JWH-133 and WIN55,212-2 on inhibition of proliferation of A375 cells(p＞0.05).
(3) JWH-133 and WIN55,212-2 inhibit the migration and invasion of A375 cells. JWH-133 and WIN55,212-2 of 1umol/L concentration has significantly smaller area than that of control group(p＜0.05).No significantly difference between JWH-133 and WIN55,212-2 on corr-migration area and trans-memberance quantity(p＞0.05).
(4) Different concentration with JWH-133 and WIN55,212-2 (1umol/5umol/10umol/L) stimulate A375 cells after 24h,48h and 72h,with mRNA and protein levels significantly(p＜0.05) downregulating levels of VEGF.The inhibition effect has shown time and dose-dependent relationship.
(5) JWH-133 and WIN55,212-2 of 1umol/L concentration stimulate A375 cells after 24h,48h and 72h and induce apoptosis.Apoptosis index(AI) of JWH-133 is 7.22%、9.17%and 11.45%;WIN55,212-2 is 6.45%、8.12%and 10.34%;Control group is 6.35%、6.09%and 6.39%respectively.The AI is significantly higher than that of control group(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
2.in vivo
(1)Treatment of JWH-133 and WIN55,212-2 inhibit the tumor growth and the inhibition ratio is 43.14%and 39.47%respectively.
(2)Treatment of JWH-133 and WIN55,212-2 significantly upregulates CB-R2 expression in mRNA and protein levels in tumor tissue(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
(3) Treatment of JWH-133 and WIN55,212-2 significantly downregulates levels of VEGF in mRNA and protein levels in tumor tissue(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
(4) Treatment of JWH-133 and WIN55,212-2 induces apoptosis in tissue levels.AI of JWH-133,WIN55,212-2 and Control was 12.84%,11.57%and 7.33% respectively.The AI is significantly higher than that of control group(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
Conclusions
1.Cannabinoid receptor 2 participate the onset process of MM.
2.JWH-133 and WIN55,212-2 significantly inhibit A375 cells proliferation, migration and invasion.
3.JWH-133 and WIN55,212-2 induce A375 cells apoptosis in vitro and vivo.
4.JWH-133 and WIN55,212-2 can inhibit angiogenesis and control the growth of tumor by downregulating levels of VEGF.
5.JWH-133 and WIN55,212-2 have no significant difference in inhibiting A375 cell proliferation,migration,invasion and induction of apoptosis in vitro and vivo.
恶性黑素瘤(malignant melanoma,MM)是一种高度恶性的肿瘤,发生隐蔽,易发生血管和淋巴结转移,发展迅速、预后差、死亡率高。删的生长和转移依赖于肿瘤内的血管生成(angiogenesis),而血管内皮生长因子(vascularendothelial growth factor,VEGF)在肿瘤血管生成机制中处于核心地位。研究表明MM血管生成十分活跃,VEGF作为最重要的促血管生成因子而逐渐成为研究热点。
已知的大麻素受体(cannabinoid receptor CB-R)分为Ⅰ型大麻素受体(cannabinoid receptor 1,CB-R1)和Ⅱ型大麻素受体(cannabinoid receptor 2,CB-R2),均为G-蛋白偶联受体(G-protein coupled receptors,GPCRs),GPCRs在肿瘤的生长和血管生成中具有重要作用。研究表明CB-R2具有抗炎症、抗增殖、抗肿瘤等作用,CB-R2激动剂体外试验可诱导细胞凋亡,体内试验可抑制肿瘤的生长而无明显的副反应。本课题组前期研究发现,CB-R2受体在MM组织中呈高表达,但对其在删中是否参予迁移、侵袭和血管生成的作用机制尚不完全明确。如能证实CB-R2激动剂具有抗血管生成和抑制肿瘤生长的功能,其可能成为治疗MM新的抗血管生成靶点药物。本课题的目的是通过体外和体内实验模型,拟证明CB-R2参与MM的发病过程,探讨CB-R2受体激动剂JWH-133和WIN55,212-2在MM中的抗肿瘤活性和抗血管生成的作用与机制,为其在临床应用提供新思路。
研究方法
1.体外实验以人恶性黑素瘤A375细胞为研究模型
应用免疫荧光检测CB-R2在A375细胞中的表达与定位;RT-PCR和Westernblot检测CB-R2在A375细胞中mRNA和蛋白水平的表达;Real time PCR和免疫组化检测CB-R2激动剂JWH-133和WIN55,212-2对A375细胞CB-R2表达的影响;MTT、划痕实验和Transwell小室模型检测JWH-133和WIN55,212-2对A375细胞增殖、迁移和侵袭作用的影响;Real-time PCR、和ELISA检测JWH-133和WIN55,212-2对A375细胞VEGF在mRNA和蛋白水平表达的影响;TUNEL检测JWH-133和WIN55,212-2对A375细胞凋亡的影响。
2.体内实验以人恶性黑素瘤A375细胞裸鼠移植瘤为研究模型
建立人恶性黑素瘤裸鼠移植瘤动物模型,观察体内成瘤情况。应用免疫荧光检测瘤组织中CB-R2的表达与定位;Real-time PCR、western blot和免疫组化检测CB-R2激动剂JWH-133和win55,212-2对肿瘤组织中CB-R2和VEGF在mRNA和蛋白水平表达的影响;TUNEL检测JWH-133和win55,212-2对肿瘤组织细胞凋亡的影响。
结果
1.人恶性黑素瘤A375细胞体外模型实验结果
①人恶性黑素瘤A375细胞在mRNA和蛋白水平均表达CB-R2,其表达定位于胞浆和胞膜,胞核无染色。②不同浓度JWH-133和WIN55,212-2(0.01/0.1/1/10/100umol/L)对A375细胞增殖具有抑制作用,48h达到高峰(P＜0.05);而两种药物对A375细胞增殖的抑制作用,经统计学分析比较无明显差异(P＞0.05)。③JWH-133和WIN55,212-2抑制A375细胞的迁移和侵袭能力;与对照组比较,1umol/L浓度JWH-133组和WIN55,212-2组细胞相对迁移面积显著降低,差异具有统计学意义(P＜0.05);1umol/L浓度JWH-133组和WIN55,212-2组细胞穿膜细胞数与对照组比较明显减少,差异具有统计学意义(P＜0.05);而两种药物组的细胞相对迁移面积和穿膜细胞数,经统计学分析比较无明显差异(P＞0.05)。④不同浓度JWH-133和win55,212-2(1umol/5umol/10umol/L)刺激A375细胞24h,48h和72h后,可降低VEGF在不同时相点mRNA和蛋白水平的表达,与对照组比较差异具有统计学意义(P＜0.05);并且这种抑制效应呈时间剂量依赖关系,JWH-133和WIN55,212-2剂量越大,刺激时间越长,VEGF表达的降低越明显。⑤1umol/L浓度JWH-133和WIN55,212-2刺激A375细胞24h,48h和72h后,可诱导A375细胞凋亡,JWH-133组A375细胞凋亡率分别为7.22%、9.1 7%和11.45%;WIN5 5,212-2组A375细胞凋亡率分别为6.45%、8.12%和10.34%;而对照组凋亡率为6.35%、6.09%和6.39%,JWH-133组和WIN55,212-2组与对照组凋亡率比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。
2.人恶性黑素瘤A375细胞裸鼠移植瘤模型实验结果
①JWH-133和WIN55,212-2可以抑制人恶性黑素瘤裸鼠移植瘤的生长,抑瘤率分别为43.14%和39.47%。②予JWH-133和WIN55,212-2,肿瘤组织可在mRNA和蛋白水平上调CB-R2的表达,与对照组比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。③JWH-133和WIN55,212-2在mRNA和蛋白水平降低肿瘤组织中VEGF的表达;与对照组比较,差异具有统计学意义(P＜0.05);两种药物之间经统计学分析比较无明显差异(P＞0.05)。④JWH-133和WIN55,212-2可诱导肿瘤组织中肿瘤细胞凋亡,对照组、JWH-133组和WIN55,212-2组肿瘤组织凋亡率分别为7.33%、12.84%和11.57%。JWH-133组和WIN55,212-2组与对照组凋亡率比较,差异具有统计学意义(P＜0.05);而两种药物之间经统计学分析比较无明显差异(P＞0.05)。
结论
1.大麻素Ⅱ型受体CB-R2参与了MM的发病过程;
2.JWH-133和WIN55,212-2可以抑制A375细胞增殖、迁移和侵袭的能力;
3.体外和体内实验模型中,JWH-133和WIN55,212-2可诱导MM肿瘤细胞凋亡:
4.体外和体内实验模型中,JWH-133和WIN55,212-2可降低MM肿瘤细胞和组织VEGF的表达和分泌,抑制血管生成,控制肿瘤的生长;
5.JWH-133和WIN55,212-2在抑制恶性黑素瘤细胞增殖、迁移、侵袭能力以及促进细胞凋亡等作用机制方面,二者无显著差异。
Research Background and Objectives
Malignant melanoma(MM) causes the greatest number of worldwide skin cancers related to deaths.It may lead to rapid invasion and blood vessel and lymph metastasis.Proangiogenesis factor vascular endothelial growth factor(VEGF) is the core of angiogenesis mechanism.Researches have shown that MM angiogenesis is so active that tumor cells stimulate the proliferation,migration and tubulogensis of endothelial cells by producing large amount of VEGF and thus lead to angiogenesis of malignant tumor.Therefore,VEGF has been one of the frontiers in MM research in the mechanism of antiangiogenesis.
There are at least two types of cannabinoid receptor,cannabinoid receptor 1 (CB-R1) and cannabinoid receptor 2(CB-R2) both G- protein coupled receptors(GPCRs).GPCRs plays an important role in the development and angiogenesis of malignant tumors.Researches have shown that CB-R2 agonist have effect on apoptosis in vitro and inhibit the growth of tumor in vivo and downregulation expression in VEGF.Our previous studies have shown that CB-R2 has high significance expression in MM,but it is yet unknown whether CB-R2 contributes to migration,invasion and angiogenesis in MM.The study is to investigate the effect of CB-R2 agonist JWH-133 and WIN55,212-2 in human malignant melanoma cell line A375 and xenografted malignant melanoma in nude mice,trying to find whether they have the effect of antiangiogenesis by regulating the expression of VEGF.Thus,it is to provide the novel targets for the treatment of MM.
Methods
1.Study on human malignant melanoma cell line A375 in vitro
Firstly,we detect the expression and location of CB-R2 in A375 cell line by immunofluorescence,finding the effect of CB-R2 agonist JWH-133 and WIN55,212-2 on the expression of CB-R2 mRNA and protein levels by Real-time PCR,immunohistochemistry and Western blot.Then,we explore the inhibitory effect of CB-R2 agonist in antiproliferation,migration and invasion by MTT, wound-healing and Transwell chamber.Furthermore,we detecte the relationship between tumor cells growth and the production of angiogenic factors VEGF by ELISA and Real-time PCR.Finally,we study the effect on apoptosis of CB-R2 agonist by TUNEL.
2.Study on xenografting malignant melanoma nude mice model in vivo
Establish the xenografting malignant melanoma nude mice model to observe the growth of the tumor,detecting the expression and location of CB-R2 in tumor tissue by immunofluorescence.And then we study the effect of CB-R2 agonist JWH-133 and WIN55,212-2 on the expression of CB-R2 mRNA and protein in tumor tissue by Real-time PCR,immunohistochemistry and Western blot. Furhermore we detecte the relationship between tumor cells growth and the production of angiogenic factors VEGF by Western blot and Real-time PCR.Finally, we study the effect on apoptosis of CB-R2 agonist by TUNEL.
Results
1.in vitro:
(1)A375 cells have expressed the CB-R2 in mRNA and protein levels.The expression is located in kytoplasmand membrane,no dyeing on nucleus.
(2)JWH-133 and WIN55,212-2 have effect on the inhibition of A375 cells at different concentrations(0.01/0.1/1/10/100umol/L) with the peak time on 48h (p＜0.05).No significantly difference between JWH-133 and WIN55,212-2 on inhibition of proliferation of A375 cells(p＞0.05).
(3) JWH-133 and WIN55,212-2 inhibit the migration and invasion of A375 cells. JWH-133 and WIN55,212-2 of 1umol/L concentration has significantly smaller area than that of control group(p＜0.05).No significantly difference between JWH-133 and WIN55,212-2 on corr-migration area and trans-memberance quantity(p＞0.05).
(4) Different concentration with JWH-133 and WIN55,212-2 (1umol/5umol/10umol/L) stimulate A375 cells after 24h,48h and 72h,with mRNA and protein levels significantly(p＜0.05) downregulating levels of VEGF.The inhibition effect has shown time and dose-dependent relationship.
(5) JWH-133 and WIN55,212-2 of 1umol/L concentration stimulate A375 cells after 24h,48h and 72h and induce apoptosis.Apoptosis index(AI) of JWH-133 is 7.22%、9.17%and 11.45%;WIN55,212-2 is 6.45%、8.12%and 10.34%;Control group is 6.35%、6.09%and 6.39%respectively.The AI is significantly higher than that of control group(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
2.in vivo
(1)Treatment of JWH-133 and WIN55,212-2 inhibit the tumor growth and the inhibition ratio is 43.14%and 39.47%respectively.
(2)Treatment of JWH-133 and WIN55,212-2 significantly upregulates CB-R2 expression in mRNA and protein levels in tumor tissue(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
(3) Treatment of JWH-133 and WIN55,212-2 significantly downregulates levels of VEGF in mRNA and protein levels in tumor tissue(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
(4) Treatment of JWH-133 and WIN55,212-2 induces apoptosis in tissue levels.AI of JWH-133,WIN55,212-2 and Control was 12.84%,11.57%and 7.33% respectively.The AI is significantly higher than that of control group(p＜0.05) and no significantly difference between JWH-133 and WIN55,212-2(p＞0.05).
Conclusions
1.Cannabinoid receptor 2 participate the onset process of MM.
2.JWH-133 and WIN55,212-2 significantly inhibit A375 cells proliferation, migration and invasion.
3.JWH-133 and WIN55,212-2 induce A375 cells apoptosis in vitro and vivo.
4.JWH-133 and WIN55,212-2 can inhibit angiogenesis and control the growth of tumor by downregulating levels of VEGF.
5.JWH-133 and WIN55,212-2 have no significant difference in inhibiting A375 cell proliferation,migration,invasion and induction of apoptosis in vitro and vivo.
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