TABLE 3.
Anti-PCa effects and mechanisms of tocoperols and tocotrienols in cell-based studies
| Year and cells | Vitamin E forms | Key finding (IC50s) | Signaling/mechanisms |
|---|---|---|---|
| 2002; DU-1145, LNCaP, CaCo-2, SaOs-2 [66] | αT, γT, βT | ↓DU-145 cell growth by αT (25–50 μM), γT (12–25 μM), and βT (50 μM) | NA |
| 2004; LNCaP, PC-3, PREC (normal prostate cells) [67] | γT, αT, γT+δT, γT+γTE | ↓ LNCaP, PC-3 cell growth by γT (25–50μM) or γT+δT (20+10 μM), γT+γTE (20+2.5 μM), but not αT; ↑ apoptosis in LNCaP cells; no effects on normal cells | ↑cytochrome C release, caspase-9 cleavage; ↑ dihydroceramides and dihydrosphingosine, which contributes to anti-PCa |
| 2004; PC-3 [68] | αT, γT, α-CEHC, γ-CEHC, trolox | ↓PCa cell growth by γ-CEHC≈γT (<10 μM) > α-CEHC>αT | ↓cyclin D1 |
| 2004; DU-145, LNCaP [69] | γTE | Combining γTE and statin synergistically ↓ PCa cell growth | NA |
| 2008; LNCaP, PC-3, PZ-HPV-7 [70] | αT, βT, γT, δT, αTE, βTE, γTE, δTE | ↓ PCa (but not immortalized cells) growth by δTE (41 μM), γTE (32 μM), βTE (54 μM) >γT, δT>αT, αTE; γTE+docetaxel showed synergy | ↑apoptosis, G1 arrest; ↓NF-κB, EGF-R and Id family proteins |
| 2011; LNCaP, PC-3; [61] | γT, γTE | ↓ LNCaP, PC-3 cell growth by γTE (10–20 μM); ↑apoptosis, autophagy and necrosis; ↑cytochrome C, PARP cleavage, LC-3; ↓p-AKT after apoptosis started | ↑ dihydroceramides and dihydrosphingosine prior to cell death; inhibiting synthesis of sphingolipids counteracted γTE’s anti-PCa |
| 2011; PC-3, DU145 [62] | γTE | γTE (7–12 μM) ↓CD133/CD44 (CSC markers), spheroid formation; CSC-rich population is sensitive to γTE | γTE may target prostate CSCs |
| 2011; PC-3, LNCaP [71] | αT, γT, δT, αTE, γTE, δTE | ↓ PC-3 cell growth by δTE (∼23 μM), γTE (30 μM) >>γT, δT>αT, and LNCaP is also sensitive to γT or δT; ↑caspase 3 | ↑ PPAR-γ, 15-LOX-2 mRNA and protein; ↓TGFβ2, NF-κB and p-p38 |
| 2014; LNCaP, VCaP, and CWR22Rv1 [64] | αT, γT, δT, or γ-TmT | δT > γT, γTmT > αT ↓ PCa cell growth, PSA and AR reporter activity; ↑apoptosis | NA |
| 2016; DU145, PC-3, C4-2, LNCaP, CWR22Rv-1 [72] | αT, δT, γT | ↓ PCa cell growth, δT (30 μM) > γT (>50 μM) >> αT; δT ↑caspase 3; ↓phosphorylation of AKT (p-AKT) | δT ↓ EGF/IGF-induced p-AKT possibly via blocking EGFR-stimulated PI3K/AKT signaling |
| 2017; LNCaP [73] | γT, δTE | γT+δTE strengthened anti-PCa and enhanced apoptosis | NA |
| 2017; PREG, LNCaP, RWPE-1 [74] | αT | αT (40 μM) ↑ the growth of RWPE-1 organoids, but not healthy prostate epithelial organoids, ↓LNCaP organoids | αT rescue detachment associated decrease in ATP synthesis and fatty acid oxidation in RWPE-1 |
| 2019; PC-3, C4-2B [75] | γTE | ↓Angiopoietin (Ang)-1 mRNA and protein; ↓CD49f and Bmi-1 (stemness markers); synergy of γTE+Tie-2 inhibitor for ↓cell growth and ↑p-AMPK | γTE+Tie-2 inhibitor may be a novel anti-PCa agent |
| 2019, 2020; PC-3, DU145 [76,77] | δTE | δTE ↑ER stress, autophagy and related p-JNK and p-p38; ↑vacuolation and apoptosis; ↑Ca2+ overload in cytosol and mitochondria, ↓mitochondria function | NA |
| 2022; PTEN-Cap8, PC-3, DU145, 22Rv1, LNCaP [55] | αT, γT, δT, γTE, δTE | ↓ PCa cell growth by δTE (12 μM) > γTE (17 μM) > αTE (26 μM), δT (24 μM) > γT (49 μM) > αT; ↑apoptosis (caspase 3) | δTE did not show strong inhibition of p-AKT |
| 2022; DU145 [78] | αT | αT (10–30 μM) ↑ cell migration and proliferation, prosurvival signaling, and PD-L1 | Upregulation of PD-L1 by αT via activating ERK and STAT3 |
| 2022; DU145 [79] | βTE | βTE dose-dependently ↓ PD-L1 and JAK2/STAT3, and T cell–mediated toxicity against DU145 | NA |
| 2024; DU145 [80] | αT, γT, δT, βT, αTE, γTE, δTE, βTE | γTE, δTE, βTE dose-dependently ↓ PD-L1; dTE promoted T cell toxicity against DU145 | δTE (20 or 30 μM) ↓ glycosylated PD-L1 in cells and exosome |
Abbreviations: C4-2B/22RV1, CRPC cells; CRPC, castration-resistant prostate cancer; CSC, cancer stem cell; ER, endoplasmic reticulum; p-JNK, phosphorylated c-Jun N-terminal kinase; PD-L1, programmed death ligand 1; PREG, healthy prostate epithelial cells; prostate cancer cell lines, LNCaP (androgen dependent); PC-3, DU145 (androgen independent); RWPE-1, HPV-18 immortalized prostate epithelial cells; ↓, suppress or inhibit; ↑, increase or enhance; ↔, show no effect.