Table 1.
Molecular mechanism targeted by curcumin in vivo and in vitro against androgen-dependent and androgen-independent prostate cancer.
| Molecular Target | Cell Lines/In-Vivo | Molecular Mechanism Modulated by Curcumin | Reference |
|---|---|---|---|
| Androgen receptor (AR) | LNCaP | Downregulated AR expression via limiting the binding activity to the ARE of the PSA gene | [100,101] |
| LNCaP | Inhibited cell proliferation and growth via modulation of AR and its signalling pathway | [102] | |
| LNCaP | Inhibited tumour growth and suppressed the PSA level by the activation of AR and interleukin-6 | [100] | |
| LNCaP & PC-3 | Downregulated AR expression and transcriptional activity | [103] | |
| LNCaP & TRAMP model |
Decreased intracellular prostate testosterone level | [102] | |
| PC-3 | Reduced AR availability by altering the over-expressed heat shock protein (Hsp90) | [104] | |
| LNCaP xenograft | Delayed the tumour growth and suppressed AR expression | [105] | |
| LNCaP xenografts | Inhibited AR through the modulation of Wnt/ß-catenin signalling | [106] | |
| LNCaP & PC-3 | Downregulated the activation of AR-related cofactors | [100,103] | |
| LNCaP | Initiated apoptosis and downregulated the AR activity | [93] | |
| LNCaP | Reduced NKX3.1 and AR expression | [107] | |
| NF-κB | LNCaP & DU145 | Suppress NF-κB expression thus abrogates their survival mechanisms | [92] |
| PC-3 | Inhibited cell proliferation and induced apoptosis via suppressed NF-κB expression | [108] | |
| LNCaP | Suppressed cell proliferation through downregulation of cyclin D1 by inhibiting NF-κB | [92] | |
| PC-3 | Enhanced cytotoxicity by suppressed constitutional and TNF-α-induced NF-κB activation | [109] | |
| PC-3 mouse model | Prevented metastasis by downregulating CXCL-1 and -2 by targeting NF-κB signalling | [110] | |
| LNCaP, PC-3 & DU145 | Sensitised PCa cells towards TRAIL-induced apoptosis | [111,112] | |
| LNCaP | Initiated apoptosis by effecting intrinsic and extrinsic pathways | [111] | |
| LNCaP | Induced cytotoxicity by inhibiting phosphorylation and degradation of IκBα | [111] | |
| LNCaP & PC-3 | Combination of TRAIL inhibits Akt-regulated NF-κB and NF-κB-dependent anti-apoptotic proteins | [113] | |
| LNCaP & PC-3 | Chemosensitization to TRAIL therapy inhibited a constitutively active NF-κB, AP-1 and active anti-apoptotic Akt (p-Akt) | [112,113,114] | |
| PC-3 xenograft model | Combination with TRAIL inhibition the growth indicated by NF-κB and AP-1 inhibition | [115] | |
| Activating protein-1 (AP-1) | PC-3 & LNCaP | Suppressed tumour progression of AP-1, which indicated by the reduced colony forming ability in soft agar | [92,103] |
| PC-3 | Exhibited anti-cancer effects by impeding AP-1 protein | [108] | |
| LNCaP | Promoted cell cycle arrest and apoptosis by regulating the level of c-Jun proteins, which is activated via phosphorylation by the c-Jun amino terminal kinase (JNK) | [116,117] | |
| LNCaP | Reduced cell proliferation and migration by suppressing the activation of AP-1 which stimulated by hydrogen peroxide | [118] | |
| DU145 | Disruption of the survival pathways by sensitising the cells, thus potentiating TNF-induced apoptosis | [92] | |
| PI3K/Akt | LNCaP | Apoptosis and cell cycle arrest by downregulating PI3K/Akt/mTOR pathway | [119] |
| LNCaP, DU145 & PC-3 | Apoptosis by downregulating PI3K p110 and p85 subunits, and phosphorylation of Ser 473 Akt. | [120] | |
| PC-3 | Decreased PI3K activity mediated by changes in the phosphorylation status of Akt | [96] | |
| PC-3 | Inhibited the phosphorylation of Akt, mTOR, and their downstream substrates which directly affect the downstream of PI3K and PDK1 activities | [121] | |
| DU145 | Suppressed cell proliferation by inhibiting Akt/mTOR signalling | [121,122] | |
| Bcl-2 family | LNCaP | Induced apoptosis in concentration-dependent manner | [120] |
| LNCaP | Initiated apoptosis by translocation of Bax and p53 to mitochondria, the production of ROS, the release of mitochondrial proteins, and activation of caspase-3 | [120,123] | |
| LNCaP implanted nude mice | Induced apoptosis | [94] | |
| PC-3 & DU145 | Apoptosis and autophagy, mediated by cell cycle arrest at G2/M phase | [124] | |
| DU145 | Induced apoptosis by suppressing the Bcl-2 expression, while activating procaspase-3 simultaneously | [125] | |
| PC-3 nude mice model | Apoptosis by upregulating Bax and downregulating Bcl-2, and regulating the mitochondrial outer membrane permeability | [126] | |
| PC-3 | Apoptosis by mitochondria damage and cell ceramide accumulation | [127] | |
| PC-3 | Increased apoptotic cell death mediated by caspase activation and the loss of mitochondrial membrane integrity | [128] | |
| PC-3 | Induced the apoptosis proteins by inhibition of NF-κB and NF-κB-regulated anti-apoptotic genes products through suppression of Akt | [113] | |
| Cyclin D1 | LNCaP | Inhibited growth through cell cycle arrest indicated by downregulation of cyclin D1 expression via inhibition of CDK4-mediated phosphorylation of Rb protein | [92] |
| LNCaP & PC-3 | Induced cell cycle arrest at G1/S, followed by apoptosis | [97] | |
| LNCaP & PC-3 | Induced cell cycle arrest at G2/M phase | [129] | |
| DU145 | Induced G0/G1 arrest by suppression of cyclin D1 and CDK2 expression, while upregulating p21 and p27 | [125] | |
| LNCaP xenograft model | Suppressed cell proliferation by downregulating cyclin D1 and upregulating TRAIL-R1/DR4, TRAIL-R2/DR5, Bax, Bak, p21 and p27 proteins | [130]. | |
| LNCaP & LNCaP xenograft model | Downregulated cyclin D1 expression through inhibition of ß-catenin accumulation | [102,106]. | |
| LNCaP | Inhibiting ligand-induced activation for EGFR and its intrinsic tyrosine kinase activity associated with cyclin D1 downregulation | [131] | |
| PC-3 | Inhibited the EGFR phosphorylation | [132] | |
| Wnt/ß -catenin | LNCaP | Inhibited cell growth by reducing the level TCF-4, CBP, and p300 proteins that leads to the decrease of ß-catenin/TCF-4 transcriptional activity thus decreased β-catenin expression | [70,133] |
| LNCaP | Inhibited cancer growth by suppressing the Wnt/ß-catenin signalling pathway | [102,106] | |
| LNCaP | Inhibited cell proliferation by suppressing the GSK-3β phosphorylation thus inducing the degradation of β-catenin | [102] | |
| MiRNA | DU145 | Inhibited cancer growth and migration by upregulating the expression of miR-143 | [34,134] |
| LNCaP, PC-3 & DU145 | Inhibited cell proliferation and migration by restoring miR-143/miR-145 cluster expression | [135,136] |
Abbreviations: Androgen receptor (AR) signalling, Activating protein-1 (AP-1), Phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), Wingless (Wnt)/ß-catenin signalling, and molecular targets; Nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and Cyclin D1.