TABLE 2.
Pharmacological effects of polyphenol phytochemicals on the JAK-STAT signaling pathway.
| Phytochemical name | Source of experimental evidence | Mechanism and effect | Effect | References |
|---|---|---|---|---|
| Apigenin | The human colon cancer cell lines HT29, DLD-1, COLO320, and HCT116 | Inhibited STAT3 phosphorylation. | Inhibition of STAT3 phosphorylation, resulting in downregulation of antiapoptotic proteins Mcl-1 and Bcl-xL and induces programmed cell death in colon cancer cells. | Maeda et al. (2018) |
| Adult male BALB/c mice | Decreased the levels of IL-4, IL-5, IL-13, and interferon-γ. Attenuated OVA-induced alterations in STAT6 and SOCS1 mRNA expressions. | It plays an anti-allergic role in allergic rhinitis (AR). | Chen et al. (2020) | |
| Luteolin | Human pancreatic cancer cell lines | Inactivated p-STAT3 and downregulated STAT3 in a dose-dependent manner. | Luteolin inhibit pancreatic cancer cell invasion by inhibiting STAT3 signaling and secretion of EMT and MMP. | Huang et al. (2015) |
| Human breast cancer MDA-MB-231 cells | Suppressed STAT3. | Luteolin enhances paclitaxel-induced apoptosis through inhibition of the STAT3 signaling pathway by mediating Fas expression and activation of caspases. | Yang et al. (2014) | |
| Gastric cancer (GC) cells | Inhibits STAT3 activation and dephosphorylated STAT3. | Luteolin selectively kills gastric cancer cells that are overactivated by STAT3, and these cells are usually drug-resistant. | Song et al. (2017a) | |
| Kaempferol 7-O-β-D-glucoside (KPG) | The RAW 264.7 murine macrophage cell line | Inhibits the phosphorylation of JAK1 and JAK2. | KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated macrophages. | Lee et al. (2018) |
| Quercetin | SJL/J mice | Blocked IL-12 signaling. | In vitro treatment of activated T cells with quercetin blocks IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STA T3, and STA T4, resulting in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. | Muthian and Bright (2004) |
| The human cholangiocarcinoma (CCA) cell lines | Inhibited IL-6 and IFN-γ and reduced p-STAT1, and STAT3 proteins in a dose-dependent manner. | Quercetin and EGCG are beneficial in inhibiting the JAK-STAT cascade in CCA cells. | Senggunprai et al. (2014) | |
| Human microvascular endothelial cells | Inhibition of miR-216a blocked the JAK2-STAT3 pathway. | Quercetin mainly inhibits survival, migration, and VEGF expression, and promotes apoptosis of HMEC-1 cells. | Wang et al. (2020) | |
| Hesperidin and 5,7,3ʹ-triacetyl hesperetin (TAHP) | Adult male Wistar albino rats | Decreased p-JAK2 and p-STAT3 and increased SOCS3 protein level. | Cinnamaldehyde and hesperetin counteract TNBS-induced ulcerative colitis through modulation of the JAK2-STAT3-SOCS3 pathway. | Elhennawy et al. (2021) |
| Male Sprague-dawley rats | Decreased STAT3 and JAK2. | TAHP play a crucial role in the pathogenesis of AA by regulating the production of proinflammatory cytokine IL-6 in serum and synovial tissue and inhibiting the over-activation of the JAK2-STAT3 signaling pathway. | Ren et al. (2013) | |
| Silibinin | A/J male mice | Decreased the phosphorylation level of STAT3. | By inhibiting the activation of HIF-1α, NF-κB, and STAT3, lung tumor growth was inhibited. | Tyagi et al. (2009) |
| Human prostate carcinoma DU145 cell | Inhibited constitutively active STAT3. | It effectively inhibited the constitutive activation and apoptosis induction of STAT3 in DU145 cells | Agarwal et al. (2007) | |
| Epigallocatechin-3-gallate (EGCG) | Human MDA-MB-231 (TNBC-derived) cell | Inhibited p-STAT3. | EGCG prevented a STAT3-mediated paracrine oncogenic control of triple-negative breast cancer cell invasive phenotype | Gonzalez Suarez et al. (2021) |
| Human oral cancer cells | Inhibited p-JAK1/2 and suppressed STAT1 translocation to the nucleus. | Indoleamine 2,3-dioxygenase, an immunomodulatory protein, is suppressed by EGCG via blocking of gamma-interferon-induced JAK-PKC-delta-STAT1 signaling in human oral cancer cells. | Cheng et al. (2010) | |
| Formononetin (FN) | The C2C12 mouse myogenic progenitor cells | Decreased JAK1-STAT1 phosphorylation level. | FN treatment activates myogenic differentiation by increasing p38MAPK and decreasing JAK1-STAT1 phosphorylation levels. | Soundharrajan et al. (2019) |
| The human colon carcinoma cell lines SW1116 and HCT116 | Reduced p-STAT3 protein level. | FN suppresses cell proliferation and invasion by inhibition of cyclin D1 and MMP2/9 expression via p-STAT3 inactivation in colon carcinoma cells. | Wang et al. (2018) | |
| HuVecs | Inhibited the phosphorylation and the mRNA expression levels of JAK2 and STAT. | FN may be a new potential therapeutic compound for the treatment of vascular complications of diabetes. | Zhou et al. (2019) | |
| Human MM cell line U266 and human myeloma cell line RPMI 8226, athymic nu/nu female mice | Inhibited the cascade of STAT3 and STAT5 signals. | FN shows anticancer effect in MM. | Kim et al. (2018) | |
| Genistein | Balb/c mice | Inhibited STAT6. | Modulates the Th1/Th2 reaction by inhibiting GATA-3 and STAT6 production while increasing T-bet production. | Gao et al. (2012) |
| Murine J774 macrophages | Inhibited activation of STAT1. | Genistein inhibited LPS-induced STAT-1 expression. | Hämäläinen et al. (2007) | |
| Malvidin | THP1 human monocytic cells | Suppressed STAT3 phosphorylation and nuclear translocation. | Malvidin inhibits the JAK-STAT pathway and blocks inflammation. | Baba et al. (2017) |
| α-Bromo-2′,3,4,4′-tetramethoxychalcone (α-Br-TMC) | Ba/F3 and Ba/F3-1*6 cells | α-Br-TMC inhibited JAK2 and STAT5 phosphorylation. | A-BR-TMC can be used in the treatment of STAT5-related malignancies. | Pinz et al. (2014) |
| 3,4,2′,4′-tetrahydroxychalcone (Butein) | Human multiple myeloma (MM) U266 | Inhibited the activation of JAK1/2. | Inhibition of tumor cell proliferation and reversal of chemotherapy resistance in multiple myeloma cells by blocking STAT3 activation. | Pandey et al. (2009) |
| Bavachin | IM9 cells, RPMI 8226 cells, and RPMI 1788 cells. Male BALB/c mice | Inhibited activation of STAT3. | Bavachin induces apoptosis by inhibiting the activation of NF-κB and STAT3 in multiple myeloma cell lines. | Takeda et al. (2018) |
| Hep3B cells | Inhibited STAT3 promoter activity. | Bavachin treats inflammatory diseases by inhibiting the activation and phosphorylation of STAT3 induced by IL-6. | Lee et al. (2012) | |
| Cardamonin | Female ICR mice | Inhibited the activation of STAT1 – 4. | Targets the production of IFN- and thereby suppresses the STAT pathway to mitigate inflammation. | Takahashi et al. (2011) |
| The human colon cancer cell line HT-29 and SW-460, and C57BL/6 mice | Reduced the secretion of IL-1β and TNF-α, and inhibited the phosphorylation of STAT. | In the treatment of recurrent colitis and colitis-related tumors. ABU can inhibit cell viability and inflammatory cytokines of colorectal cancer cells in vitro. | Hou et al. (2019) | |
| CD133+GSCs | Inhibited the activation of STAT3 and the expression of downstream STAT3 genes, and prevented the migration of STAT3 to the nucleus and dimerization. | Cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. | Wu et al. (2015) | |
| 5,7-Dihydroxyflavone | Human hepatocellular carcinoma (HepG2) and BALB/c female nude mice | Decreased the phosphorylation of STAT3. | The phosphorylation level of STAT3 was decreased, the antiapoptotic signal was weakened, and the growth of xenograft of HepG2 tumor was significantly inhibited. | Zhang et al. (2013) |
| Ginkgetin (GK) | C57BL/6 male mice and 3T3-L1 | Inhibited STAT5 activity. | The inhibition of PPARγ and C/EBPα expression by Ginkgo biloba flavonoids was due to STAT5 inactivation at the initial stage of adipogenesis. | Cho et al. (2019) |
| Human cancer cell lines HCT-116, DU-145, LNCap and PC-3 | Mediated dephosphorylation of STAT3. | Ginkgetin blocks its entry into the nucleus, which in turn inhibits STAT3-mediated gene expression, thus inhibits the proliferation of DU-145 prostate cancer cells. | Jeon et al. (2015) | |
| Giant cell tumor samples | Inhibited STAT3 phosphorylation. | Ginkgetin significantly reduced survivin expression, which significantly inhibited tumor growth. | Xiong et al. (2016) | |
| Casticin (CST) | 786-O, HEL 299 | Inhibited p-JAK1/2 and the expression of the phosphorSrc kinase | Casticin inhibits the JAK-STAT pathway in tongue squamous cell carcinoma, hypertriploid renal cell carcinoma, and oral squamous cell carcinoma. | Lee et al. (2019) |
| Kurarinone | The immortalized human keratinocyte cell line HaCaT and C57BL/6 mice or OT-II transgenic mice | Inhibitory phosphorylation of STAT1, STAT3, STAT5, and STAT6. | Suppresses JAK/STAT-dependent CD4+T-cell differentiation and improves chronic inflammatory skin diseases by inhibiting pro-inflammatory mediators, the JAK-STAT pathway, and the general immune response. | Kim et al. (2013) |
| Resveratrol | Sprague-dawley rats | Downregulated the p-JAK, p-STAT, and inflammatory cytokines. | Resveratrol protects hippocampal neurons from cerebral ischemia/reperfusion injury and alleviates cognitive dysfunction by regulating JAK-ERK-STAT signaling pathway. | Chang et al. (2018a) |
| BTBR T+ Itpr3tf/J (BTBR) and C57BL/6 male mice | Decreased the expression levels of IL-6, TNF-α, IFN-γ, p-STAT1, and p-STAT3 (Tyr705). | Resveratrol can also inhibit JAK1-STAT3 in the brain tissue of autistic mice and treat neuroimmune dysfunction. | Ahmad et al. (2018) | |
| RAW 264.7 macrophages | Inhibited the transcriptional activity and phosphorylation of STAT1. | Resveratrol controls the inflammatory response of interferon-γ-activated macrophages. | Chung et al. (2011) | |
| Caffeic acid (CA) and Caffeic acid phenethylester (CAPE) | The Caki-I human renal carcinoma and COS7 monkey kidney cell lines | Suppressed p-STAT3 and STAT3-inducible VEGF gene expression. | CA and CAPE suppress tumor angiogenesis by inhibiting the activity of STAT3 and the expression of HIF-1α and VEGF | Jung et al. (2007) |
| SHRSP and WKY rats | Abolished the tyrosine phosphorylation of JAK2 and STAT1. | CA attenuated the proliferative response of SHRSP and WKY rat vascular smooth muscle cells to Ang stimulation by partially blocking the JAK-STAT signaling cascade and the RAS/RAF-1/ERK1/2 cascade. | Li et al. (2005) | |
| Male wistar rats (Rattus norvegicus) | Downregulated cerebral JAK2 expression, STAT3 phosphorylation, and SOCS3 protein expression. | CAPE can reduce oxidative stress and inflammation in the brain of rats, enhance antioxidant defense ability, and reverse the upregulation of Chromium (VI) on JAK2, STAT3 and SOCS3 in brain tissues. | Mahmoud and Abd El-Twab (2017) | |
| Anwulignan | Human NSCLC cell lines A549, H1299, H1650, and H1975. | Inhibited the phosphorylation of STAT3 by directly targeting JAK1. | Anwulignan is a novel JAK1 inhibitor that may have therapeutic implications for NSCLC management. | Xie et al. (2021) |
| Honokiol | Human oral squamous cell carcinoma (OSCC) cell line | Reduced the levels of p-JAK2 and p-STAT3. | Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like associated cells. | Huang et al. (2016) |
| Breast cancer cells | Induced increase in tumor suppressor LKB1 led to dephosphorylation and inactivation of STAT3. | HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. | Sengupta et al. (2017) | |
| Human leukemia cell lines (HEL and THP1) | Inhibited STAT3 transcription activity, reduced nuclear translocation of STAT3, and decreased STAT3 target gene expression. | HNK plays an anticancer role in acute myeloid leukemia by inhibiting STAT3 signaling. | Bi et al. (2015) | |
| Curcumin | Sprague dawley male rats | Enhanced SOCS-1 expression. | The anti-inflammatory effect of curcumin is realized by enhancing SOCS-1 expression and inhibiting the JAK-STAT pathway. | Zhang et al. (2016) |
| Human OS cell line (MG-63) | Inhibited p-JAK2 and p-STAT3. | Curcumin inhibits the JAK-STAT pathway to induce G0/G1 phase arrest and apoptosis, and inhibits the proliferation and migration of osteosarcoma cells. | Sun et al. (2019b) | |
| Wedelolactone | HepG2, WiDr, A431, and A549 cells | Specifically inhibited TCPTP, the major phosphatase of STAT1, and prolonged IFN-γ-induced STAT1 phosphorylation. | Wedelolactone enhanced the antitumor effect of IFN-γ by inhibiting TCPTP-mediated STAT1 dephosphorylation. | Chen et al. (2013) |