Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis.
Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis.
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DOI：
10.1371/journal.pone.0257984
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Mitra R
中科院分区：
文献类型：
--
作者：
Vetrichelvan O;Gorjala P;Goodman O Jr;Mitra R
前列腺癌是美国男性癌症相关死亡的第二大原因。已经开发了几种疗法来治疗晚期前列腺癌，但这些疗法往往有严重的副作用。为了以更少的副作用改善结果，我们重点研究了呋喃香豆素佛手苷，这是一种在西柚汁中发现的天然产物，也是一种有效的细胞色素P3A抑制剂。我们最近的研究表明，抑制CYP3A5可以阻断雄激素受体(AR)信号，而AR信号对前列腺癌的生长至关重要。我们观察到，佛手柑通过减少总AR和核AR(AR激活)，减少下游AR信号，从而减少前列腺癌(PC)细胞的生长。通过共聚焦显微镜研究和前列腺癌标志物前列腺特异性抗原(PSA)水平的降低，证实了佛手参素在减少AR激活方面的作用。进一步研究表明，佛手柑可促进细胞周期阻滞，并使G0/G1期细胞积聚。细胞周期阻滞伴随细胞周期蛋白D、细胞周期蛋白B、CDK4、P-cdc2(Y15)和P-Wee1(S642)的减少。我们还观察到佛手柑能触发前列腺癌细胞系的凋亡，这一点通过TUNEL染色和PARP裂解得到了明显的证明。我们的数据表明，佛手柑可能会抑制前列腺癌的生长，特别是在携带野生型CYP3A5的非裔美国人(AA)患者中，这些患者往往表现为侵袭性疾病。
Prostate cancer is the second leading cause of cancer related death in American men. Several therapies have been developed to treat advanced prostate cancer, but these therapies often have severe side effects. To improve the outcome with fewer side effects we focused on the furanocoumarin bergamottin, a natural product found in grapefruit juice and a potent CYP3A inhibitor. Our recent studies have shown that CYP3A5 inhibition can block androgen receptor (AR) signaling, critical for prostate cancer growth. We observed that bergamottin reduces prostate cancer (PC) cell growth by decreasing both total and nuclear AR (AR activation) reducing downstream AR signaling. Bergamottin’s role in reducing AR activation was confirmed by confocal microscopy studies and reduction in prostate specific antigen (PSA) levels, which is a marker for prostate cancer. Further studies revealed that bergamottin promotes cell cycle block and accumulates G0/G1 cells. The cell cycle block was accompanied with reduction in cyclin D, cyclin B, CDK4, P-cdc2 (Y15) and P-wee1 (S642). We also observed that bergamottin triggers apoptosis in prostate cancer cell lines as evident by TUNEL staining and PARP cleavage. Our data suggests that bergamottin may suppress prostate cancer growth, especially in African American (AA) patients carrying wild type CYP3A5 often presenting aggressive disease.
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DOI：
10.1186/1478-811x-8-31
发表时间：
2010-12-22
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Chaitanya GV;Steven AJ;Babu PP
通讯作者：
Babu PP
影响因子：
5.9
作者：
Bower JJ;Vance LD;Psioda M;Smith-Roe SL;Simpson DA;Ibrahim JG;Hoadley KA;Perou CM;Kaufmann WK
通讯作者：
Kaufmann WK
影响因子：
6.6
作者：
Gaston, KE;Kim, D;Mohler, JL
通讯作者：
Mohler, JL
影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
影响因子：
3.7
作者：
Dugrand-Judek A;Olry A;Hehn A;Costantino G;Ollitrault P;Froelicher Y;Bourgaud F
通讯作者：
Bourgaud F