Table 4.
Molecular targets and major mechanism of action of PEITC in various cancer types
| Cancer type |
Mechanism | Molecular Targets | Outcome | Concentration and duration |
Model used | Reference |
|---|---|---|---|---|---|---|
| - | Epigenetic | CYP2E1 | Reduced activation of carcinogens | 25, 50μM | Escherichia coli MV1304 (c DNA CYP2E1) | [89] |
| - | Thiol modification | Topoisomerase IIα | Apoptosis | 2.5, 5, 10μM (6h) | Top2β+/+; top2β−/− primary MEFs | [175] |
| Breast | Protein suppression | BIM, PUMA, BCL2, BCL-xl, BAX, Bak, | Apoptosis | 2.5, 5μM (24h) | BRI-JM04; MDA-MB-231; MCF-7; HCT- 116; HCT-116 (PUMA −/−) | [136] |
| Synergism with paclitaxel | - | Apoptosis; G2/M cell cycle arrest | 1–10μM (24, 48h) | MCF7; MDA-MB-231 | [190] | |
| Protein suppression | HSP90, HSF1, Cyclin B1, CDK1, Cdc25C, PLK-1, and p21, caspase 3, 9 | Apoptosis; G2/M cell cycle arrest | 0.1, 0.5, 2.5, 5μM (24h) | MCF7; MDA-MB-231 | [192] | |
| Protein suppression | BCL2, BAX, NRF2, GSH, caspase 3, 8 and 9 | Apoptosis; G2/M cell cycle arrest | 20μM (2, 4, 6, 24, 48h) | MCF7; BT549; MDA-MB-231; ZR-75-1; SKBR3; T47D | [171] | |
| Protein suppression | p70S6K, Akt, NDRG1, HSP70, ERK, AMPK, 4E-BP1, mTORC1 | Proliferation inhibition | 0–20μM (3,4h) | MCF-7; PTEN deficient MEF; TSC2 deficient MEF | [194] | |
| Chemoprevention | - | Reduced tumor incidence and increased tumor free survival | 50 μmol/kg or 150 μmol/kg every 2 days (pre-tumor initiation); PEITC continued (18 weeks) | NMU induced breast cancer in Sprague Dalwey rats | [85] | |
| Chemoprevention | - | Angiogenesis inhibition and tumor growth inhibtion | 3 μmol/g diet (29 weeks) | MMTV-neu mice | [86] | |
| Epigenetic changes | PARP-1, BCL-2, Bax, Cdk-1, Cyclin B1, α-tubulin, β-tubulin, acetyl-α-tubulin | Increase in Taxol (10, 100nM) sensitivity | 5, 10μM (24h) | MCF-7; MDA-MB-231 | [191] | |
| Genetic expression | P57, CYP19, BRCA2, IL2, ATF2, p53, Hsp27 | - | 3μM (48h) | MCF-7 | [123] | |
| ROS | HER2, EGFR, Akt, STAT3, BIM, BAX, BCL-XL, XIAP, | Proliferation inhibition; apoptosis; reduced tumor growth | 5, 10, 15μM (24h) | MCF-7; MCF-7 high HER2; MDA-MB-231; MDA-MB-231 high HER2; MDA-MB-231 high HER2 xenograft in athymic nude mice | [102] | |
| Breast and prostate | Protein suppression | Vimentin | Migration inhibition; apoptosis; tumor growth inhibition | 2.5, 5μM (6, 12, 24h); 3 μmol PEITC/g diet (29 weeks) | MDA-MB-231; PC-3; DU145; MMTV-neu mice | [156] |
| Cervical | Protein suppression | DR4, DR5, HO-1, cytochrome c, clusterin, claspin, cIAP1, cIAP2, catalase, Bcl2, Bcl-xl, BAX, BAD, Bid, ERK, JNK, MEK | Apoptosis | 2.5, 5, 10μM (48h) | HEp-2; KB | [141] |
| Cervical, Breast | Synergism with cisplatin | MAPKs, MEK1/2, NFkB, Bcl2, Bcl-xl, BAX, NOXA, PUMA, DR4, DR5, TRAIL | Apoptosis | 5μM (2, 4, 8, 12, 24h) | HeLa; C33A; MCF-7 | [200] |
| Cholangio carcinoma | Increase of free calcium level in cytosol | Cyt c, BCL-XL, BAX, AIF | Apoptosis | 1, 3, 10μM (3, 6h) | KKU-M214; Chang cells (reference) | [133] |
| ROS | Cyt c, BCL2, caspases 3, 8, 9, AIF | Apoptosis | 3, 10μM (3, 6, 24h) | KKU-100 | [135] | |
| Colon | ROS | DDB2 | Tumor regression | 10μM (0.5, 1, 2, 4, 6, 12h) | HCT116; HCT116 expressing control shRNA or DDB2 shRNA xenograft | [139] |
| Colon and blood | Epigenetic (Histone modification and genetic modulations) | NFkB, STAT1, chemokines, MMPs | Proliferation inhibition | 2.5, 5, 10, 15μM (5, 8, 12, 18h) | SW480; HT-29; THP-1 | [189] |
| Gastric | ROS; Rhodamine- 123; Cisplatin resistance reversal | ERCC1, survivin, and Mad2, Akt, NfkB, Glutathione, PGP, MRP1 | Apoptosis; cell cycle arrsest, Cisplatin resistance reversal | 1, 5μM (24h) | SGC7901/DDP | [201] |
| Glioma | ROS; Sensitization to TRAIL | DR5, p53, caspase 3, 8 and 9 | Apoptosis | 2.5μM (24h) | U87MG; A172; U343; T98G | [199] |
| Glioma, prostate, colon, liver, breast | Sensitivity to hypoxia | HIF1α, VEGF, ERK, Akt, MMP2, MMP9, uPA, | Apoptosis | 1, 2.5, 5μM (8, 16h) | U87; DU145; HCT116; HepG2; SKBR3 | [154] |
| Leukemia | Protein suppression | Akt, JNK, XIAP, MCl1, BCL2, BCL-XL, BAD, BAX | Apoptosis; tumor growth suppression | 2, 4, 6, 8μM (0–24h); 50 mg/kg, i.p. (20 days) | U937; HL-60; Jurkat cells | [116] |
| Immune-modulation | CD3, CD19, Mac-3 | Enhanced phagocytic activity of macrophages; Increased NK cell activity; Enhanced T cell proliferation | 80 & 160 mg/kg (2 weeks) | WEHI-3; BALB/c mice | [162] | |
| ROS, nitric oxide | Mitochondrial complexes, peroxiredoxin III (Prx III), superoxide dismutase-2 (SOD-2), Bcl-2, Glutathione peroxidase 4, NDUSF3 | Apoptosis | 10μM (1, 3, 6, 12h) | HL-60; Raji | [169] | |
| Lung | Epigenetic (Covalent protein binding) | Actin, Tubulin, Tropomyosin, HSP’s, Vimentin, ADAM7, thioredoxin etc. | - | 20μM (1h) | A549 | [114] |
| Cytoskeletal changes | F-actin, α-tubulin, | Apoptosis; G2/M cell cycle arrest | 1–10μM (24 & 72h) | A549; H1299 | [126] | |
| Epigenetic | Tubulin | Cell growth inhibition and apoptosis | 5, 10, 20μM (4h) | A549 | [176] | |
| Genetic expression | AP1, JNK, p38 MAPK, p44/42 MAPK, cyclin B1 | Apoptosis; G2/M cell cycle arrest | 12.5, 20μM (24h) | L9981 | [188] | |
| Post translational modification | p53 (mutant) | Apoptosis | 15, 20μM (0–24h) | H596; MDA- MB-231; | [195] | |
| Lung, colon, ovarian | ROS; Sensitization of platinum resistant cells | GSH | Reduced cell survival | 5, 7.5 μM (6, 12, 24h); 25mg/kg (bid, once a week-3 weeks) | A549; A549/CDDP; THC8307; THC8307/L-OHP; HCT116; A2780; A549/CDDP xenografts in BALB/c nude mice | [155] |
| Myeloid leukemia | ROS | Fas, Fas ligand, caspase 9 and 3 | Apoptosis | 5, 10, 15, 20μM (24, 48, 72h) | K562 | [143] |
| Melanoma | ROS, ER stress | CDC25C, CDK1, Chk1, Chk2, cyclin A, Wee1 p53 and p21 (a); Bax, Bcl2 and Bid (b); Apaf- 1, caspase-9 and -3, PARP, AIF and Endo G (c); GRP 78 and GADD153 (d); caspase- 8, Fas and FasL (e); i- NOS, catalase, SOD (Cu/Zn) and SOD (Mn) | Apoptosis; G2/M cell cycle arrest | 5–20μM (24–48h) | A375.S2 | [193] |
| Multiple Myeloma (MM) | Protein suppression | AIF, XIAP, MCL1, Survivin, Hsp70 Hsp90, | Apoptosis; G2/M cell cycle arrest; tumor growth suppression | 1.56–20μM (12, 24, 48h); 60mg/kg (34 days) | RPMI 8226-S; RPMI-Dox40; RPMI-MR20; RPMI-LR5; OPM-1; OPM-2; MM.1S; MM.1R cells; the non-transformed human liver epithelial cell line THLE-3; the human bone marrow stromal cell line HS-55; primary MM cells purified from bone marrow aspirates of MM patients or healthy donors | [122] |
| Myeloma | ROS; Proteasomal activity inhibition | p53, IkBα | Proliferation inhibition | 10, 20, 40μM (0–24h) | U266; RPMI-8226; A549 | [127] |
| Oral | Protein suppression | DR5, caspase 8, BID, p38 | Proliferation inhibition; apoptosis | 7.5, 15, 20μM (48h) | HN22; HSC-2; HSC-4; YD-15; Mc-3 | [140] |
| ROS | p53, p27, p21, CDK2, Cyclin E, p15, Cdc25a, CDK6, Cyclin D, AIF, NFkB, GRP78 | Apoptosis; G0/G1 cell cycle arrest | 0.5, 1, 2, 2.5, and 5 μM (24, 48h) | HSC-3 | [121] | |
| Oral squamous carcinoma | Protein suppression | EGF receptor signaling, MMP2, 9, Akt, ERK, PDK1, PI3K, IkBα, JNK, p38 | Invasion inhibition | 1, 2μM (24h) | OSCC SAS | [157] |
| Ovarian | Protein suppression | EGFR, Akt, mTOR, complex, | Apoptosis; tumor growth inhibition | 2.5–40μM (24h); 12μmol/mouse | SKOV-3; OVCAR-3; TOV-21G | [117] |
| ROS; combination effect with metformin | - | Proliferation inhibition | 5μM (24h) | OVCAR3; CAOV3; SKOV3; PA-1; A2780; A2780cis | [197] | |
| Pancreatic | Protein suppression | Bcl-2 and Bcl-XL, upregulated the proapoptotic protein Bak, and suppressed Notch 1 and 2 levels | Apoptosis; G2/M cell cycle arrest; tumor growth delayed | 2.5, 5, 10μM (24h); 12 μmol/day (5 days/wk – 1wk pre-inoculation) | MIAPaca2; PL- 45; BxPC3; MIAPaca2 xenograft | [134] |
| ROS, miRNA | miR-27a/miR-20a:miR-17-5p, Sp1, Sp3, Sp4, CD1, VEGF, c-Myc | Apoptosis | 10, 20μM (24h) | Panc28; L3.6PL; Panc1; SW480; RKO; | [184] | |
| Prostate | Protein suppression | ITGB1, ITGA2, ITGA6 | Proliferation inhibition; tumor growth inhibition | 0.1, 1, 5μM (24h); 3 μmol/g diet (2 weeks) | LNCaP; xenograft | [179] |
| Protein suppression | P53, Wee1, Cdc25c, caspases 3, 8, 9, FAS, AIF, cytochrome c, Bcl2, BAK, BID, GRP78, GADD153 | Apoptosis; G2/M cell cycle arrest | 10μM (6, 12, 24, 48h) | DU 145 | [124] | |
| Autophagy | p62, LC3 | Apoptosis; Tumor growth suppression | 3 μmol PEITC/g diet (19 weeks) | Mouse model | [148] | |
| DNA Fragmentation | XIAP, Survivin | Proliferation inhibition and apoptosis | 0–5μM (6, 12, 24h) | PC-3; LNCaP | [144] | |
| miRNA and transcriptional activity | Androgen receptor, miR-17, PCAF | Proliferation inhibition | 10–20μM (24–48h) | LNCaP; PC-3; DU145; C4–2B PCa; ALVA31 | [183] | |
| Mitchondrial structure, autophagy | Mitochondria, β-tubulin | Apoptosis | 8μM (4–18h) | LNCaP | [146] | |
| Gene expression | Insulin-like growth factor binding protein 3, fibronectin, thyroxine degradation enzyme, and integrin β6 | Tumor growth suppression | 3μmol/g diet (7 weeks) | LNCaP | [161] | |
| Prostate, head and neck | Protein suppression | TLR3, IRF3, | Inhibition of anchorage independent growth and colony formation; tumor growth inhibition | 2.5, 5, 10μM; 3μmol/g diet (19 weeks) | HEK293; HEK293 derived TLR3 expressing stable cells (Wt11); RL24 cells; HT1080 cells; RAW264.7 cells; SV40 T antigen expressing FVB MEF; PCI15A; LNCaP; C57/BL6 mice | [163] |
| Sarcoma | ROS, DNA damage | Cyclin A, Cyclin B1, Chk1, p53, catalase, iNOS, Mn-SOD, AIF, cytochrome c, caspase 9 and 3 | Apoptosis; G2/M cell cycle arrest | 5, 7.5, 10, 15μM (12, 18, 24h) | U-2 OS | [125] |