Table.
Biochemical basis of anticancer effects of carnosol
| Molecular mechanisms | Experimental models | References |
|---|---|---|
| Inhibition of carcinogen metabolism | ||
| ↓B[α]P-DNA adduct formation, ↓gene expression and activity of CYP1A1, ↑expression of GST-pi and QR enzymes | Incubation of B[a]P-stimulated BEAS-2B cells with carnosol (1 μg/mL) for 6 or 24 hr | Offord et al.18 |
| ↓B[α]P-DNA adduct formation, ↓mRNA and protein expression of CYP1A1 and CYP1B1, ↓Hsp90-ATPase activity, ↓AhR expression | Human oral leukoplakia (Msk-leuk1) or HaCaT cells treated with carnosol (5 or 10 μM) prior to incubation with B[α]P | Mohebati et al.19 |
| Induction of cytoprotective proteins | ||
| ↑Intracellular glutathione level, ↑gene expression of GCLC and GCLM, ↑nuclear localization of Nrf2, ↑Nrf2-ARE reporter gene activity | Carnosol treatment (5 or 10 μM) of HepG2 cells | Chen et al.29 |
| ↑HO-1 mRNA and protein expression, ↑HO-1 promoter activity, ↑phosphorylation of Akt, ↑nuclear localization of Nrf2, ↑Nrf2 binding to the ho-1-ARE promoter sequence, ↓H2O2-induced cell death | PC12 cells treated with 10 μM carnosol | Martin et al.28 |
| Attenuation of inflammatory responses | ||
| ↓Expression of iNOS protein and mRNA, ↓phosphorylation of p38 MAP kinase and ERK, ↓IKK activity, | Treatment of LPS-stimulated murine macrophage 264.7 cells with carnosol (5, 10 or 20 μM) | Lo et al.32 |
| ↓IκBα phosphorylation, ↓nuclear localization of c-Rel and p65, ↓NF-kB DNA binding and reporter gene activity | ||
| ↓Expression of COX-2 protein and mRNA, ↓production of PGE2, ↓phosphorylation of ERK, p38 MAP kinase and JNK, ↓PKC activity, ↓binding of AP-1 to cox-2 promoter | Carnosol (20, 40 or 60 μM) treatment of human mammary epithelial 184B5/HER cells | Subbaramaiah et al.34 |
| ↓Phorbol ester-induced mouse ear inflammation, ↓mRNA expression of COX-2, IL-1β, and TNF-α | Topical application of carnosol (10 or 20 μg/cm2) to mouse skin treated with TPA | Mengoni et al.35 |
| ↓LPS-induced NO production | Incubation of LPS-stimulated murine Raw264.7 macrophages with carnosol (12.5 or 25 μM) | |
| Inhibition of tumor cell proliferation and induction of apoptosis | ||
| Induction of G2/M phase cell cycle arrest, ↓expression of cyclin-A, -D1, D-2, Cdk-2, -4 -6, and Bcl-2, ↑expression of Bax, p21 and p27, ↓phosphorylation of mTOR, p70S6 kinase and Akt, ↑phosphorylation of AMPKα, and 4EBP1, activation of caspase-8, and caspase-9 | Treatment of PC3 prostate cancer cells with carnosol (20, 40, and 60 μM) | Johnson et al.38 |
| Induction of subG1 arrest, ↑caspase-3 activity | HL-60 cells treated with carnosol (25 or 50 μM) | López-Jiménez et al.39 |
| ↓Cell proliferation and the expression of AR | Treatment of LNCaP and 22Rv1 prostate cancer cells with 20 or 40 mM carnosol | Johnson et al.12 |
| Interacts with ligand binding domain of ERα, ↓Cell proliferation and the expression of ERα, | Treatment of NCF-7 breast cancer cells with 20 or 40 μM carnosol | Johnson et al.12 |
| ↓Cell viability and induces apoptosis, activation caspase -9 and caspase-3, cleavage of PARP, ↑generation of ROS, ↑expression of p53 and Bax, ↓phosphorylation of JAK2, Src and STAT3, ↓STAT3 DNA binding activity and the reporter gene activity, ↓expression of cyclin D-1, D-2 and survivin | HCT116 colon cancer cells incubated with carnosol (50 or 100 μM) | Park et al.42 |
| Suppression of angiogenesis, cell migration and invasion | ||
| ↓Migration and capillary tube formation, and ↓MMP-2 activity | Incubation of bronchial aortic endothelial cells and HUVECs with carnosol (25 or 50 μM) | López-Jiménez et al.39 |
| ↓TNFα-induced cell migration by blocking the expression of MMP-9 | TNFα-stimulated vascular smooth muscle cells treated with carnosol | Chae et al.44 |
| ↓Cell migration and invasion of melanoma cells. ↓phosphorylation of MAP kinases and Akt, ↓activation of NF-κB and AP-1, ↓MMP-9 expression and activity | B16/F10 melanoma cells treated with 5 or 10 μM carnosol | Huang et al.45 |
B[α]P, benzo[α]pyrene; CYP1A1, cytochrome p450 1A1; GST-pi, glutathione-S-transferase-pi; QR, quinine reductase; Hsp90, heat shock protein 90; AhR, arylhydrocarbon receptor; HaCaT, human keratinocyte; GCLC, glutamate cysteine ligase catalytic subunit; GCLM, glutamate cysteine ligase modifier subunit; Nrf2, nuclear factor erythroid-related factor-2; HO-1, heme oxygenase-1; Akt, Akt/protein kinase B (PKB); ARE, antioxidant response element; iNOS, inducible nitric oxide synthase; MAP, mitogen-activated protein; IKK, inhibitor kappa B (IκB) kinase; NF-κB, nuclear factor-kappa B; LPS, lipopolysaccharide; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun-N-terminal kinase; PKC, protein kinase C; AP-1, activator protein-1; IL-1β, interleukin 1β; TNF-α, tumor necrosis factor α; NO, nitric oxide; TPA, 12-O-tetradecanoyl phorbol-13-acetate; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2-associated X protein; mTOR, mammalian target of rapamycin; AMPKα, 5’-AMP activated kinase-α; 4EBP1, 4E-binding protein-1; PC3, prostate cancer.