TABLE 3.
Mechanisms and chemopreventive effects of citrus peel extract flavonoids on cancer cell lines1
| Flavonoids | Chemopreventive and anti-inflammatory effects | Mechanisms | Cancer cells | References |
|---|---|---|---|---|
| Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) | Cell cycle regulation | Arrested cell cycle progression at G1 | MDA-MB-435, MCF-7, HT-29, KATO-III, TMK-1, A549, MKN-45, MKN-74 | 39, 68, 142,130, 170–172 |
 |
Antiangiogenesis, anti-inflammatory, antimetastasis | Inhibited the activity of extracellular signal regulated kinases 1/2 (ERK1/2) phosphorylation and c-JNK and activation of the caspase pathway | MDA-MB-435, MCF-7, HT-29 | |
| Co-chemotherapeutic | Increased cytotoxicity of doxorubicin | MCF-7, T47D | ||
| Suppression of carcinogenesis | Inhibited the activity of CYP1A2 | MCF-7, T47D | ||
| Antioxidant | Scavenge DPPH radicals, hydrogen peroxide scavenging, hydroxyl radical scavenging | — | ||
| Antimetastasis | Prevented the migration of A549 cancer cells | A549 cells in vitro/in vivo | ||
| Apoptosis | Downregulated (Bcl-2)/upregulation (Bax) | HeLa, THP-1 | ||
| Anti-inflammation | Decreased activation of AP-1, NF-κB, and CREB | RAW 264.7 monocyte/macrophage-like cells | ||
| Anti-inflammation | Prohibited the LPS-induced mRNA and protein expression of iNOS | Skin inflammation | ||
| Anti-inflammation | Induced the expression of COX-2 by suppressing UVB | Human keratinocytes in vitro | ||
| Antimetastatic | Inhibited MEK1/2 activity is associated with the suppression of pro-MMPs | Human fibrosarcoma HT-1080 cells | ||
| Antimetastatic | Enhanced the expression of TIMP-1 by the activation of PKCβII/epsilon-JNK pathway | Human fibrosarcoma HT-1080 cells | ||
| Antiproliferation | Decreased differentiation into granulocytes and macrophages by TNF-α | Murine myeloid leukemia WEHI 3B cells | ||
| Tangeretin (4′,5,6,7,8‐pentamethoxyflavone) | Antioxidant | Scavenge DPPH radicals, hydrogen peroxide scavenging, hydroxyl radical scavenging | — | 111, 133, 136, 170, 173–177 |
 |
Antioxidant | Inhibited the activity of CYP1A1 and the expression of mRNA | Human intestine Caco-2 cells | — |
| Apoptosis | Triggered apoptosis via p53 pathway | COLO 205, HL-60 cells | ||
| Antiproliferation | Decreased the expression of PROM1 and SNAI1 | Cancer stem cell of HT29 | ||
| Antiproliferation, apoptosis | Activated caspase-3 | Cocon LOvo/DX cells | ||
| Co-chemotherapeutic | Increased cytotoxicity of doxorubicin | MCF-7, T47D | ||
| Cell cycle regulation | Arrested cell cycle at G1 by targeting p53, p21, and p37 pathway | MCF-7, MDA-MB-435, colon cancer line HT-29, upregulate COLO 205 cells | ||
| Anti-inflammation | Blocked AKT activation | Lung carcinoma cells | ||
| Anticarcinogenic | Inhibited P450 1A/1A2/3A4 | Human liver microsome cells | ||
| Antimetastatic | Decreased the number of metastatic nodules in Lentini model | Melanoma B16F10 cells | ||
| Anticarcinogenic | Reduced PhIP-DNA adduct formation in colon | Colon cancer cells | ||
| Anti-inflammation | Induced LPS-induced NO production | RAW 264.7 cells | ||
| Anti-inflammation | Inhibited IL-1β-induced production of COX-2 by the activation of JNK, AKT, ERK, and p38 MAPK | A549, H1299 | ||
| Sinensetin (5,6,7,3′,4′-pentamethoxyflavone) | Cell cycle arrest | Induced cells in G0/G1 phase | HUVEC | 149, 178–186 |
|
Antiangiogenesis | Downregulated the mRNA expression of angiogenesis flt1, hras, and kdrl | Zebrafish | |
| Antiproliferation, apoptosis | Inhibited iNOS expression, NO production, and PGE2 production | — | ||
| Cell cycle regulation | Inhibited in S phase by DNA elongation | T47D breast cancer cells | ||
| Antiproliferation, cell cycle block | Captured cells G2/M phase and increased apoptosis, increased the expression of p53 and p21 | AGS gastric cancer cells | ||
| Anti-inflammatory | Inhibited inflammatory gene expression and STAT1 activation, inhibited iNOS, NO, and PGE2 production | Carrageenan-induced paw inflammation in the rat | ||
| Apoptosis | Reactivated oxygen species production, DNA damage, gene 153 expression, caspase activation | Leukemia cells | — | |
| Antiproliferation | Activated Ca2+-dependent apoptotic proteases | MCF-7 breast cancer cells | ||
| Apoptosis | Upregulated caspase-3, -8, -9, and poly(ADP-ribose), polymerase (PARP) cleavage | T-cell lymphoma Jurkat cells | ||
| Induced autophagy and cell death | Activated reactive oxygen species/c-Jun N-terminal kinase (JNK), blocked Akt/mTOR | T-cell lymphoma Jurkat cells | ||
| Cell cycle arrest | Arrest cells at G0/G1 population | HepG2 cells | ||
| Apoptosis | Downregulated Bcl-xL, upregulated TRAIL and PTEN | HepG2 cells | ||
| Hesperetin (3′,5,7-trihydroxy-4′-methoxyflavanone) | Apoptosis | Induced apoptosis by activation of caspase-3 | HL-60 cells | 39, 86, 187–193 |
|
Antiproliferation | Inhibited oxidative stress and DNA damage | HT-29 colon adenocarcinoma | |
| Anticarcinogenic | Downregulated the HIF-1a/VEGF/VEGFR2 pathway | Xenograft C6 glioma cells in rats | ||
| Cell cycle arrest | Decreased cyclin D1, CDK4 and Bcl-xL by upregulating the level of p57Kip2 | MCF-7 cancer cells | ||
| Antimetastatic | Induced COX-2, MMP-2, and MMP-9 | DMH-induced colon cancer in rat; B16-F10 murine melanoma cells | ||
| Apoptosis | Activated the mitochondrial pathway by rising concentrations of ROS, Ca2+, and ATP in mice | Xenograft tumors in mouse model of gastric cancer | ||
| Apoptosis, antiproliferation | Suppressed the expression of NF-kB, p38, and caspase-3 | PC-3 prostate cancer cells | ||
| Cell cycle arrest | G2/M arrest by controlling the concentration of cyclin B1, CDC2, CDC25C, and p21 | A549 lung cancer, MCF-7 | ||
| Apoptosis | Increased the expression of caspase-3, -8, -9, p53, Bax, and Fas death receptor | Cervical cancer SiHa, A549 lung cancer, HL-60 cells | ||
| Apoptosis | Induced via Bax-dependent mitochondrial pathway | HT-29 cells | ||
| Naringin (4′,5,7-trihydroxyflavanone-7-rhamnoglucoside) | Cell cycle regulation | Upregulated p21, G1-phase arrest, activated Ras/Raf/ERK-mediated, decreased cyclin D1 and cyclin E | 5637 bladder cancer cells, MDA-MB-231 xenograft mice | 96, 194–200 |
 |
Metastasis, anticarcinogenic | Inhibited the activity of PI3K/Akt/mTOR and upregulated p21CIP1/WAFI | AGS cells | |
| Cell cycle arrest | Cell cycle arrest in S phase | HT-29 | ||
| Antiproliferation, antioxidant | Modulated gene expression, decreased DNA methyltransferase activity, downregulated the expression of Bcl2 and Bcl-xL | SKOV3 ovarian cancer cells | ||
| Cell cycle arrest | Increasing p21 and arrest in G1 of cell cycle; inhibited the activity of CDK2 | MCF-7 | ||
| Antiproliferative | Inhibited CYP3A4, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 | |||
| Antiproliferation, apoptosis | Decreased the mRNA expression of BID, BAX, caspase-3, cytochrome c, p53, p21, and p27 | DU145 prostate cancer cells | ||
| Apoptosis | Enhanced the expression of caspases, p53, Bax, and Fas death receptor | HT-29 | ||
| Antimetastasis | Downregulation of MMP-9 and repressed the PI3K/AKT/mTOR/p70S6K signaling pathway | MCF-7 | ||
| Antiproliferation | Upregulated EGFR and ERK phosphorylation | HeLa and A549 cells | ||
| Antiproliferation, apoptosis | Suppressed the NF-κB/COX-2/caspase 1 | HeLa | ||
| Hesperidin (hesperetin-7-rutinoside) | Antiproliferative | Inhibited MMP-9 by NF-κB and AP-1 signaling | NALM-6 leukemia cells | 187, 188, 201–206 |
 |
Apoptosis | Inhibited the PI3K/Akt pathway through PTEN-phosphatase | SUN-C4 colon cancer cells | |
| Antimetastatic, angiogenesis | Suppressing ANGPT1 gene | Laryngeal cancer cells | ||
| Upregulated the level of p21 and p53 | MCF-7 cells | |||
| Antiproliferation | Inhibition of JAK/STAT signaling pathway | Cutaneous skin cancer cells | ||
| Apoptosis | Inhibited Aurora-A and Akt-mediated GSK-3β/β catenin cascade | A431 skin cancer cells | ||
| Antioxidant | Upregulated Nrf2 (nuclear factor-2) | Cutaneous skin cancer cells | ||
| Anti-inflammation | Downregulated mRNA expression of various cytokines (TNF, IL-1, IL-6) | Cutaneous skin cancer cells | ||
| Anti-inflammation | Inhibited IL-6, TNF, COX-2, iNOS inflammatory components | A431 skin cancer cells | ||
| Antiproliferation | Upregulated BAX and downregulated Bcl-2, decreased the release of cytochrome c | HeLa cervical cancer cells, A2780 ovarian cancer cells | ||
| Co-chemotherapeutic | Inhibited PgP activity | Human leukemia cells (CEM/ADR5000) |
1
Akt, serine specific protein kinase; ANGPT1, angiopoietin 1; AP-1, activator protein 1; Bax, Bcl2-associated X protein; Bcl, B-cell lyphoma; Bcl-xL, Bcl2-associated extra large protein; BID, a proapoptotic protein; CDK, cyclin-dependent kinase; COX, cyclooxygenase; CREB, c-AMP response element binding protein; CYP, cytochrome P450; DPPH, 2,2-diphenyl-1-picrylhydrazyl; EGFR, epidermal growth factor receptor; ERK, extracellular signal regulated kinase; Fas, a receptor protein of the TNF receptor family; flt, vascular endothelial growth factor receptor 1; GSK, glycogen synthase kinase; HIF, hypoxia inducible factor; hras, transforming protein p21; HUVEC, human umbilical vein endothelial cell; iNOS, inducible nitric oxide synthase; JAK, Janus-like kinase; JNK, c-Jun N-terminal kinase; kdrl, vascular endothelial growth factor receptor kdr-like; Kip2, cyclin-dependent kinase inhibitor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MMP, matrix metalloproteinase; mTOR, mechanistic target of rapamycin; PgP permeability glyoprotein; PhIP, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PROM, prominin-1; PTEN, phosphatase and tensin homolog; p21CIP1/WAFI, cyclin-dependent kinase inhibitor 1; P450, cytochrome P450; Raf, a serine/threonine-specific protein kinase; Ras, reticular activating system; ROS, reactive oxygen species; SNAI, sodium-coupled neutral amino acid transporter 1; STAT, signal transducer and activator of transcription; TIMP, tissue inhibitor of metalloproteinases; TRAIL, TNF-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.