姜黄素对前列腺癌PC-3M细胞作用的实验研究
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摘要
前列腺癌在接受内分泌治疗12～18个月后会转变为雄激素非依赖性前列腺癌(AIPC),对于AIPC患者尚缺乏有效的治疗手段。姜黄素是一种有开发前景的天然抗肿瘤新药。目前国内外关于姜黄素对前列腺癌作用的研究较少,对雄激素非依赖性前列腺癌的研究更是鲜见报道。本研究选取了雄激素非依赖性前列腺癌细胞系PC-3M为研究对象,通过体内外实验探讨了姜黄素对雄激素非依赖性前列腺癌的作用及其机制,结果显示:姜黄素在体外能抑制PC-3M细胞的生长、诱导细胞凋亡;抑制PC-3M细胞的粘附、侵袭能力。在体内对PC-3M裸鼠皮下移植瘤生长有抑制作用。本研究为进一步探讨姜黄素对AIPC的抗肿瘤机制奠定了理论基础,并为AIPC的临床治疗拓展了新的思路。
Prostate cancer is the most frequently diagnosed malignant tumor in male in western countries. Prostate cancer is the first place in incidence of malignancy and the second leading cause of cancer-related deaths in American males,just secend to lung cancer. Recently, along with the prolonging of the average life and the changing of life style, the incidence and mortality of prostate cancer in China have increased gradually than before. Most patients with early-state prostate cancer are asymptomatic, approximately 40% of prostate cancers have spread to distant sites and lost the potentially curable chance when diagnosed at first. Since the discovery by Huggins in 1941 that androgen ablation benefited patients with prostate cancer, endocrine androgen -ablation therapy has become a dominating method of prostate cancer.But the response to androgen-ablation therapy is transient, and the majority of prostate cancers relapse to the status of androgen independence after 12 to 18 months,resulting in death. Patients with androgen -independent prostate cancer have short -term survival. Despite the availability of various therapeutic approachs, none has provided a marked therapeutic effectiveness for such patients.Therefore,investigation of novel therapies for androgen-independence prostate cancer is urgently needed.
Curcumin is hydroxybenzene pigment extract and purify from rhizome of curcuma,the major pharmaceutical effect including anti-inflammation,antioxidant, dropping blood lipid,anti -atheroscherosis,anti-tumor and so on. National cancer research center of American has already select the curcumin as third generation tumor preventive drug.The anticancer properties of curcumin on a broad range of tumors in vivo and vitro have been demonstrated and meanwhile the anti- invasion and anti- metastasis properties. The anti tumor features of curcumin is becoming hot research target for its high efficiency and low toxicity.A few reports places stress on prostate cancer, there are few reports about androgen -independent prostate cancer. We make human prostate carcinoma PC-3M cells as our research object, exploring anti tumor effects and mechanism of cucurmin on androgen -independent prostate cancer.
I.The effects of curcumin on proliferation inhibition and apoptosis of human prostate carcinoma PC-3M cell
The cells were divided into 4 treatment groups(10、20、30 and 40umol·L-1 curcumin) and control group, treated with different time and by using inverse microscopy ,the morphologic alterations of PC-3M cells were observed ;inhibition of cells proliferation was detected by MTT assay ; cells cycle phase was analyzed by flow cytometry;cell apoptosis was inspected by acridine orange-ethidium bromide fluorescent staining method ;the protein levels of COX-2 and caspase-3 in carcinoma cells were observed by SP immunohistochemistry. the activities of
caspase-3 were evaluated by colorimetry. The results have demonstrated:
1. After being treated with curcumin , PC-3M cells grew round and small obviously and were against the wall in the inverse microscopy; with the increasing of the concentration of cucurmin and the elongation of the treated time,the PC-3M cell growth was inhibited ,the inhibition of proliferation of PC-3M cells in a time and dose dependent manner(p﹤0.01).
2.Partial cells presented the morphological changes of apoptosis under the fluorescent microscope,the apoptosis rates of the control group and 4 treatment groups were(9.83±1.53)%、(11.56±1.92)%、(27.83±2.52)%、(34.17±2.08)% and(38.50±2.65)%, respectively.
3. After treatment by curcumin, the cell numbers in S and G2/M phase were increased, the cell number in Go/G1 phase was decreased. the effect of curcumin on cell cycle was dose dependent.
4. with the increasing of concentration of curcumin,the COX-2 expression was decreased and the caspase-3 expression was increased ,in a dose dependent manner(p﹤0.01).In the process of the apoptosis induced by curcumin, the activities of caspase-3 increased, and with the concentration of curcumin increased, the activities of caspase-3 increased.
In conclusion, our results have revealed that Cucrmin could significantly inhibit the growth of PC-3M cells, induce apoptosis.Down-regulating COX-2 ,up-regulating caspase-3 , increasing the activities of caspase-3 and arresting cells at S and G2/M phase are probably its molecular mechanisms.
II Inhibition of adhesion and invasion of human prostate carcinoma PC-3M cell by curcumin
The cells were divided into 4 treatment groups(10、20、30 and 40 umol umol·L-1 curcumin) and control group, treated with different time and the adhesion and invasion were measured by MTT and Boyden chamber method,respectively; the protein levels of MMP-2 and TIMP-2 were observed by Western blot. The results have demonstrated:
1. The ability of PC-3M cells to adhere was decreased by curcumin, the suppressive rates of adhesion of PC-3M cells were 17.81%、30.59%、39.77% and 50.69% ,respectively.With the increasing of the concentration of cucurmin, the ability to adhere was decreased significantly, in a dose dependent manner. The ability of PC-3M cells to invade was decreased by curcumin, the suppressive rates of invasion of PC-3M cells were 22.97%、36.40%、63.84% and 69.65%, respectively.With the increasing of the concentration of cucurmin, the ability to invade was decreased significantly, in a dose dependent manner.
2. With the increasing of concentration of curcumin,the MMP-2 expression was decreased and the TIMP-2 expression was increased ,in a dose dependent manner.
In conclusion, our results have revealed that Cucrmin could significantly inhibit the ability of PC-3M cells to adhere and invade in vitro, in a dose dependent manner. The anti- invasive effect of curcumin is probably the result of down-regulation of MMP-2 and up-regulation of TIMP-2 expression.
III.The experimental study on the effects of curcumin on xenograft growth of prostate cancer cell line PC-3M
A nude mice model of xenograft PC-3M was established. Eighteen male BALB/c nude mice bearing with PC-3M were randomly divided into 3 groups with 6 mice in each group.Low dose curcumin group: the mice were treated with intraperitoneal injection of the 50mg/kg ,0.1ml for each time ,three times every week for three weeks ,a day after the transplantation of tumor tissue ;large dose curcumin group:The mice were treated with intraperitoneal injection of the 100mg/kg with the same method. control group:The mice were treated with intraperitoneal injection of the water solution containing6% anhydrous alcohol and 6% macrogol 400, 0.1ml for each time ,three times every week for three weeks ,a day after the transplantation of tumor tissue . The tumors were excised and weighed,the tumours volume ,weight and the inhibition rate were calculated. The tumor tissues were detected by pathology and the protein levels of VEGF and Survivin were detected by immunohistochemistry. The results have demonstrated:
1. The mean tumor weights of 3 groups were(0.94±0.03)、( 0.59±0.05) and (0.46±0.03)g,respectively and the mean volumes (1061±76)、(695±34) and (544±22)mm3 ,respectively. the difference in tumor weight and volume between the control and curcumin group were significant(P<0.01) and the inhibition rate were 37.23% and 51.02%, respectively.
2. The protein levels of VEGF and Survivin in tumor tissues of curcumin group were lower than of control group(P<0.01). The protein levels of VEGF and Survivin in tumor tissues of large dose curcumin group were lower than those of low dose curcumin group(P<0.01).
In conclusion, our results have revealed that curcumin could inhibit xenograft growth of prostate cancer cell line PC-3M , the possible mechanisms may be related to down-regulating VEGF to inhibit angiogenesis of tumor ;inhibiting the expression of Survivin to induce apoptosis ,inhibit proliferation of tumor and to inhibit VEGF pathway , reducing angiogenesis of tumor indirectly.
Prostate cancer is the most frequently diagnosed malignant tumor in male in western countries. Prostate cancer is the first place in incidence of malignancy and the second leading cause of cancer-related deaths in American males,just secend to lung cancer. Recently, along with the prolonging of the average life and the changing of life style, the incidence and mortality of prostate cancer in China have increased gradually than before. Most patients with early-state prostate cancer are asymptomatic, approximately 40% of prostate cancers have spread to distant sites and lost the potentially curable chance when diagnosed at first. Since the discovery by Huggins in 1941 that androgen ablation benefited patients with prostate cancer, endocrine androgen -ablation therapy has become a dominating method of prostate cancer.But the response to androgen-ablation therapy is transient, and the majority of prostate cancers relapse to the status of androgen independence after 12 to 18 months,resulting in death. Patients with androgen -independent prostate cancer have short -term survival. Despite the availability of various therapeutic approachs, none has provided a marked therapeutic effectiveness for such patients.Therefore,investigation of novel therapies for androgen-independence prostate cancer is urgently needed.
Curcumin is hydroxybenzene pigment extract and purify from rhizome of curcuma,the major pharmaceutical effect including anti-inflammation,antioxidant, dropping blood lipid,anti -atheroscherosis,anti-tumor and so on. National cancer research center of American has already select the curcumin as third generation tumor preventive drug.The anticancer properties of curcumin on a broad range of tumors in vivo and vitro have been demonstrated and meanwhile the anti- invasion and anti- metastasis properties. The anti tumor features of curcumin is becoming hot research target for its high efficiency and low toxicity.A few reports places stress on prostate cancer, there are few reports about androgen -independent prostate cancer. We make human prostate carcinoma PC-3M cells as our research object, exploring anti tumor effects and mechanism of cucurmin on androgen -independent prostate cancer.
I.The effects of curcumin on proliferation inhibition and apoptosis of human prostate carcinoma PC-3M cell
The cells were divided into 4 treatment groups(10、20、30 and 40umol·L-1 curcumin) and control group, treated with different time and by using inverse microscopy ,the morphologic alterations of PC-3M cells were observed ;inhibition of cells proliferation was detected by MTT assay ; cells cycle phase was analyzed by flow cytometry;cell apoptosis was inspected by acridine orange-ethidium bromide fluorescent staining method ;the protein levels of COX-2 and caspase-3 in carcinoma cells were observed by SP immunohistochemistry. the activities of
caspase-3 were evaluated by colorimetry. The results have demonstrated:
1. After being treated with curcumin , PC-3M cells grew round and small obviously and were against the wall in the inverse microscopy; with the increasing of the concentration of cucurmin and the elongation of the treated time,the PC-3M cell growth was inhibited ,the inhibition of proliferation of PC-3M cells in a time and dose dependent manner(p﹤0.01).
2.Partial cells presented the morphological changes of apoptosis under the fluorescent microscope,the apoptosis rates of the control group and 4 treatment groups were(9.83±1.53)%、(11.56±1.92)%、(27.83±2.52)%、(34.17±2.08)% and(38.50±2.65)%, respectively.
3. After treatment by curcumin, the cell numbers in S and G2/M phase were increased, the cell number in Go/G1 phase was decreased. the effect of curcumin on cell cycle was dose dependent.
4. with the increasing of concentration of curcumin,the COX-2 expression was decreased and the caspase-3 expression was increased ,in a dose dependent manner(p﹤0.01).In the process of the apoptosis induced by curcumin, the activities of caspase-3 increased, and with the concentration of curcumin increased, the activities of caspase-3 increased.
In conclusion, our results have revealed that Cucrmin could significantly inhibit the growth of PC-3M cells, induce apoptosis.Down-regulating COX-2 ,up-regulating caspase-3 , increasing the activities of caspase-3 and arresting cells at S and G2/M phase are probably its molecular mechanisms.
II Inhibition of adhesion and invasion of human prostate carcinoma PC-3M cell by curcumin
The cells were divided into 4 treatment groups(10、20、30 and 40 umol umol·L-1 curcumin) and control group, treated with different time and the adhesion and invasion were measured by MTT and Boyden chamber method,respectively; the protein levels of MMP-2 and TIMP-2 were observed by Western blot. The results have demonstrated:
1. The ability of PC-3M cells to adhere was decreased by curcumin, the suppressive rates of adhesion of PC-3M cells were 17.81%、30.59%、39.77% and 50.69% ,respectively.With the increasing of the concentration of cucurmin, the ability to adhere was decreased significantly, in a dose dependent manner. The ability of PC-3M cells to invade was decreased by curcumin, the suppressive rates of invasion of PC-3M cells were 22.97%、36.40%、63.84% and 69.65%, respectively.With the increasing of the concentration of cucurmin, the ability to invade was decreased significantly, in a dose dependent manner.
2. With the increasing of concentration of curcumin,the MMP-2 expression was decreased and the TIMP-2 expression was increased ,in a dose dependent manner.
In conclusion, our results have revealed that Cucrmin could significantly inhibit the ability of PC-3M cells to adhere and invade in vitro, in a dose dependent manner. The anti- invasive effect of curcumin is probably the result of down-regulation of MMP-2 and up-regulation of TIMP-2 expression.
III.The experimental study on the effects of curcumin on xenograft growth of prostate cancer cell line PC-3M
A nude mice model of xenograft PC-3M was established. Eighteen male BALB/c nude mice bearing with PC-3M were randomly divided into 3 groups with 6 mice in each group.Low dose curcumin group: the mice were treated with intraperitoneal injection of the 50mg/kg ,0.1ml for each time ,three times every week for three weeks ,a day after the transplantation of tumor tissue ;large dose curcumin group:The mice were treated with intraperitoneal injection of the 100mg/kg with the same method. control group:The mice were treated with intraperitoneal injection of the water solution containing6% anhydrous alcohol and 6% macrogol 400, 0.1ml for each time ,three times every week for three weeks ,a day after the transplantation of tumor tissue . The tumors were excised and weighed,the tumours volume ,weight and the inhibition rate were calculated. The tumor tissues were detected by pathology and the protein levels of VEGF and Survivin were detected by immunohistochemistry. The results have demonstrated:
1. The mean tumor weights of 3 groups were(0.94±0.03)、( 0.59±0.05) and (0.46±0.03)g,respectively and the mean volumes (1061±76)、(695±34) and (544±22)mm3 ,respectively. the difference in tumor weight and volume between the control and curcumin group were significant(P<0.01) and the inhibition rate were 37.23% and 51.02%, respectively.
2. The protein levels of VEGF and Survivin in tumor tissues of curcumin group were lower than of control group(P<0.01). The protein levels of VEGF and Survivin in tumor tissues of large dose curcumin group were lower than those of low dose curcumin group(P<0.01).
In conclusion, our results have revealed that curcumin could inhibit xenograft growth of prostate cancer cell line PC-3M , the possible mechanisms may be related to down-regulating VEGF to inhibit angiogenesis of tumor ;inhibiting the expression of Survivin to induce apoptosis ,inhibit proliferation of tumor and to inhibit VEGF pathway , reducing angiogenesis of tumor indirectly.
引文
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