Table 1.
Anticancer mechanisms of fisetin.
| Organs | Cell Line/Animals | IC50 [µM] |
Mechanism | Ref. |
|---|---|---|---|---|
| Bladder | Wistar rats | Nd | FIS increases in the number of TUNEL-positive cells FIS regulates the expression of apoptosis-related proteins FIS downregulates NF-κB pathways FIS upregulates the expression of ARF |
[28] |
| T24 | ≈70 # ≈90 * |
FIS inhibits the proliferation of T24 and EJ cells by inducing apoptosis and blocking cell-cycle progression in the G0/G1 phase FIS increases the expression of p53 and p21 proteins FIS decreases the levels of cyclin D1, cyclin A, CDK4 and CDK2 FIS increases the expression of Bax and Bak FIS decreased the levels of Bcl-2 and Bcl-xL FIS triggers mitochondrial apoptotic pathway |
[27] | |
| EJ | >100 * ≈80 # |
|||
| J82 | >100 * ≈80 # |
|||
| Breast | SUM159 MDA-MB-468 |
ND | FIS influences MAPK/ERK pathway to impair RNA Pol I activity and rRNA biogenesis FIS localizes to the nucleolus and reduces the number of nucleoli per cell FIS affects RNA polymerase I activity and rRNA biogenesis FIS downregulates MAPK signaling FIS inhibits functional attributes of malignant mammary tumor cells |
[18] |
| HCC1806, HCC70, HCC1937, BT-549, 20 Hs578T, MDA-MB-231, 157, 468 |
ND | FIS inhibits migration of metastatic TNBC cells FIS inhibits migration and matrix invasion of TNBC cells FIS inhibits of metastasis in zebrafish FIS targets different components and substrates of the oncogenic PI3K/AKT pathway and reduces their activities FIS disrupts activities of several protein kinases in MAPK and STAT pathways |
[87] | |
| MDA-MB-453 | ND | Fisetin induces apoptosis in HER2/neu-overexpressing breast cancer cells Fisetin increases PI3K activity at 10 µM, which gradually declines on treatment with higher concentrations (>25 µM) FIS (10 µM) increases phosphorylation of Akt in MDA-MB-453 cells FIS decreases tyrosine phosphorylation of HER2 FIS decreases the levels of HER2/neu |
[31] | |
| 4T1 JC |
ND | FIS inhibits cell migration and colony formation FIS decreases MMPs production and increases HO-1 expression Nrf2 mediates FIS-induced HO-1 expression in breast cancer cells |
[33] | |
| 4T1 | ≈80 * ≈40 # |
FIS inhibits breast cancer cell viability FIS inhibits the proliferation, migration and invasiveness of mammary carcinoma cells FIS induces the apoptosis of mammary carcinoma cells FIS regulates the PI3K/Akt/mTOR pathway in 4T1 mammary carcinoma cells FIS inhibits the primary tumor growth of 4T1 cells |
[32] | |
| MCF-7 | ≈35 * ≈35 # |
|||
| MDA-MB-231 | >100 * >100 # |
|||
| MDA-MB-231 | ≈100 * | FIS suppresses the proliferation, migration and invasion FIS reverses EMT in TNBC Cells FIS suppresses PI3K-Akt-GSK-3β signal pathway but upregulated PTEN expression |
[88] | |
| BT549 | ≈100 * | |||
| MDA-MB-231 | ND | FIS causes inhibition of cell growth in MDA-MB-231 breast cancer cells | [89] | |
| MDA-MB-468 | >100 * 100 # |
FIS inhibits breast cancer cell growth FIS inhibits TNBC cell division and cell-cycle progression FIS causes tnbc cells to undergo apoptosis FIS inhibits histone h3 phosphorylation FIS disrupts the mitochondrial membrane and causes caspase activation in tnbc cells |
[34] | |
| MDA-MB-231 | >100 * >100 # |
|||
| MCF-7 | ND | FIS attenuates TPA-induced cell invasion in MCF-7 cells FIS inhibits the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways |
[35] | |
| MCF-7 | ≈40 * | FIS exhibits substantial cytotoxicity in caspase-3-deficient MCF-7 cells FIS does not induce necroptosis in MCF-7 cells FIS induces caspase-dependent cell death in MCF-7 cells FIS induces mitochondrial depolarization and p53-independent cell death in MCF-7 cells FIS inhibits autophagy in MCF-7 cells |
[36] | |
| MDA-MB-231 | >100 * | |||
| Brain | GBM8401 | >100 * | FIS exhibits effective inhibition of cell migration and inhibits the invasion of GBM8401 cells FIS inhibits the expression of ADAM9 protein and mRNA FIS phosphorylates ERK1/2 in a sustained way |
[39] |
| T98G | 93 * 75 # |
FIS upregulates the expression of caspase-3, caspase-9, caspase-8, and bax FIS downregulates the expression of Bcl-2 and survivin |
[38] | |
| Cervix | HeLa | ND | FIS induces morphological changes and inhibits proliferation FIS changes nuclear morphology FIS leads DNA fragmentation FIS encourages G2/M arrest and modulates cell-cycle regulatory genes FIS activates extrinsic and intrinsic pathways FIS modulates expression of various pro- and anti-apoptotic proteins FIS elevates caspase-3, caspase-8 and caspase-9 activity FIS changes the aberrant MAPK and PI3K/AKT/mTOR in HeLa cells |
[90] |
| HeLa | 52 * 36 # |
FIS induces apoptosis of HeLa cells in a dose- and time-dependent manner FIS triggers the activations of caspases-3 and -8 and the cleavages of poly (ADP-ribose) polymerase FIS induces a sustained activation of the phosphorylation of ERK1/2 FIS significantly reduces tumor growth in mice with HeLa tumor xenografts |
[44] | |
| Colorectal | SW480, HCT116, HT29 | >100 * >100 * >100 * |
FIS reduces the expression of PI3K, phosphorylation of AKT, mTOR, its target proteins, constituents of mTOR signaling FIS increases the phosphorylation of AMPKα. |
[47] |
| LoVo OR-LoVo CPT11-LoVo |
>100 * >100 * ≈50 * |
FIS induces apoptosis in LoVo cells, OR-LoVo, and CPT11-LoVo cells FIS induces apoptosis and inhibits survival pathway in parental and chemoresistance colon cancer cells FIS inhibits tumor growth in nude mice |
[52] | |
| Caco-2 | ≈30 * | FIS inhibits cellular proliferation and viability of colorectal cancer cell line FIS induces apoptosis FIS inhibits PGE2 production |
[91] | |
| Mouse xenograft models | ND | FIS inhibits tumor growth in a mouse CT-26 xenograft model FIS induces p53 and suppresses securin protein expression |
[92] | |
| HCT-116 HT-29 |
ND | FIS reduces the surviving cell fraction in p53 wild-type HCT116 cells FIS prolongs radiation-induced G2/M arrest and enhanced radiation-induced cell growth arrest in HT-29 cells FIS suppresses radiation-induced phosphorylation of H2AX and phospho-Chk2 (Thr-68) in HT-29 cells FIS enhances radiation-induced caspase-dependent apoptosis in HT-29 cells FIS enhances radiosensitivity of irradiated HT-29 cells via the inhibition of AKT-ERK pathways |
[93] | |
| HCT116 | ≈540 * ≈140 # ≈130 ^ |
FIS induces growth inhibition of HCT116 and HT29 colon cancer cells FIS induces apoptosis of HT29 colon cancer cells FIS inhibits expression of COX2 in HT29 cells FIS inhibits COX2 promoter activity and PGE2 secretion FIS inhibits β-catenin pathway in HT29 cells FIS inhibits expression and translocation of TCF1 and TCF4 in HT29 cells FIS inhibits COX2 expression through downregulation of TCF4 FIS inhibits activation of EGFR in HT29 cells FIS inhibits activation of NF-κB in HT29 cells FIS reduces expression of Wnt target genes and inhibits colony formation |
[50] | |
| HT-29 | ≈240 * ≈140 # ≈57 ^ |
|||
| COLO205, HCT-116, HCT-15, HT-29 | ND | FIS with NAC increases the expression of cleaved caspase-3 and PAPR protein FIS with NAC produces greater density of DNA ladders NAC and FIS inhibits on ERK protein phosphorylation |
[51] | |
| COLO205 | >100 * | FIS inhibits cellular proliferation and viability on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors HSP90 inhibitors enhance FIS-induced cytotoxicity HSP90 inhibitors increase expression of cleaved caspase-3 and the PAPR protein Increased caspase-3 and caspase-9 activities were detected in cancer cells treated with FIS and HSP90 inhibitors |
[53] | |
| HCT-116 HT-29 |
ND | FIS exhibits higher cytotoxicity in securin-null HCT116 cells Knockdown of securin expression in cells enhances FIS-induced cell death p53-deficient human colon cells are resistant to FIS-induced apoptosis and cytotoxicity |
[48] | |
| HCT-116 HT-29 |
ND | FIS induces apoptosis of HCT-116 cells FIS induces depolarization of the mitochondrial membrane in HCT-116 cells FIS alters the levels of Bcl-2 family proteins FIS induces Bax translocation to mitochondria FIS increases cleavage of caspase-8 |
[49] | |
| HT-29 | ND | FIS inhibits both cell growth and DNA synthesis FIS decreases the activities of cyclin-dependent kinases CDK2 and CDK4 FIS inhibits CDK4 activity |
[54] | |
| Kidney | 786-O | ≈50 * | FIS decreases RCC cell viability FIS induces cell-cycle arrest in the G2/M phase FIS inhibits migration and invasion FIS inhibited CTSB, CTSS, and ADAM9 FIS upregulates ERK activation |
[57] |
| CaKi-1 | ≈30 * | |||
| ACHN | ≈40 * | |||
| A-498 | ≈40 * | |||
| Stem cells | ND | FIS inhibits HuRCSC cell division and proliferation, invasion, in vivo tumorigenesis and angiogenesis FIS decreases TET1 expression levels in HuRCSCs |
[94] | |
| CaKi | ND | FIS induces apoptosis in Caki cells FIS induces sub-G1 population and cleavage of PARP FIS induced apoptosis through upregulation of DR5 expression FIS induces p53 protein expression FIS induces upregulation of CHOP expression and ROS production |
[58] | |
| Leukemia | K562 | ND | FIS (from 10 to 50 µM) is not highly toxic to the K562 cells FIS did not cause any apparent changes in the viability FIS is not a potent inducer of apoptosis FIS-treated cells exhibits a greater capacity to invade than the untreated ones FIS treatment enhances the nuclear localization of β-catenin |
[62] |
| WEHI-3 | ND | FIS decreases total viable cells through G0/G1 phase arrest and induced sub-G1 phase FIS induces cell apoptosis by the formation of DNA fragmentation FIS induces intracellular Ca2+ increase FIS decreases the ROS production and the levels of ΔΨm FIS increases the activities of caspase-3, -8, -9 FIS reduces expressions of cdc25a FIS increases expressions p-p53, Chk1, p21 and p27 FIS inhibits Bcl-2 and Bcl-xL and increases Bax and Bak |
[64] | |
| HG-3, EHEB, | ND | FIS augments the cytotoxic activity of luteolin | [95] | |
| K562 | ≈160 # ≈120 ^ |
FIS inhibits growth of K562 cells FIS induces apoptosis of K562 cells FIS increases caspase-3 activity FIS arrests cell cycle at both S and G2/M phases |
[63] | |
| HL60 | ≈80 # ≈45 ^ |
FIS triggers apoptosis in HL60 cells FIS induces loss of mitochondrial membrane potential FIS increases caspase-3 activity FIS arrests cell cycle at the G2/M phase |
[65] | |
| THP-1 | ND | FIS affects survival of acute monocytic leukemia cells FIS-treatment results in increase in NO levels FIS-treatment induces double strand DNA breaks FIS induces NO production downregulates mTOR activity and causes activation of caspases FIS alters Ca2+ levels and activates caspases |
[67] | |
| K562 | ND | |||
| U937 | ND | |||
| HL-60 | ND | FIS induces apoptosis of K562 cells FIS causes rapid and transient induction of caspase-3/CPP32 activity FIS does not cause caspase-1 activity FIS decreases procaspase-3 protein |
[66] | |
| Liver | HepG2 | ≈80 * | FIS performs as DR2 agonist to suppress liver cancer cells proliferation, migration and invasion FIS activates caspase-3 signaling to induce apoptosis FIS downregulates VEGFR1, p-ERK1/2, p38 and pJNK |
[70] |
| HCC-LM3 | ≈40 * | |||
| SMMC-7721 | >100 * | |||
| Charles foster rats | ND | FIS normalizes the enhanced expression of TNFα and IL1α | [96] | |
| HepG2 | ND | FIS inhibits autophagy by the activation of PI3K/Akt/mTOR and modulation of AMPK signaling pathways. FIS inhibits autophagic flux in HepG2 cells. FIS inhibits autophagy through AMPK regulation FIS exposure does not show any significant ATP level changes |
[71] | |
| HepG2 | ND | FIS decreases cell viability and proliferation of HepG2 cells FIS induces cell-cycle arrest in the G2/M phase FIS induces both apoptosis and necroptosis in HepG2 cells FIS induces ROS production FIS causes a marked increase in the expression of TNFα and IKκB FIS causes a marked decrease in NF-κB, pNF-κB and pIKκB expression FIS reduces the expression of Bcl2, and elevates levels of Bax, caspase-3, and PARP |
[72] | |
| SK-HEP-1 | ND | FIS shows dose-dependent cytotoxic effects on SK-HEP-1 cells, accompanied by DNA fragmentation FIS induces cellular swelling and the appearance of apoptotic bodies FIS induces of apoptosis in SK-HEP-1 cells FIS activates Caspase-3 signaling to induce apoptosis |
[73] | |
| Lung | H1299 A549 |
ND | FIS decreases the expression of signaling proteins (β-catenin, NF-κB, EGFR, STAT-3) FIS decreases the ability of H1299 cells to form colonies and potentiates the cytotoxic effects of tyrosine kinase inhibitor-erlotinib |
[97] |
| A549 | ND | FIS inhibits A549 cell proliferation FIS causes cell-cycle arrest in A549 cells FIS induces apoptosis of A549 cells FIS suppresses cell adhesion, invasion and migration FIS inhibits the activation of the ERK signaling pathway via MEK1/2 |
[76] | |
| NCI-H460 | ND | FIS increases the ER stress signaling FIS increases the level of mitochondrial ROS FIS induces mitochondrial Ca2+ overloading and ER stress FIS induced ER stress-mediated cell death via activation of the MAPK pathway |
[78] | |
| A549 | ND | FIS acts synergistically with paclitaxel to decrease the viability of A549 cells FIS synergized with PTX or ATO in A549 cells as well as that the synergistic effect of FIS and PTX was cell line-specific FIS induces autophagy in A549 cells |
[98] | |
| A549 | ND | FIS inhibits the adhesion, invasion, and migration in A549 cells FIS inhibits the expressions of MMP-2 and u-PA FIS inhibits the phosphorylation of ERK FIS inhibits the protein expressions of MMP-2 and u-PA FIS inhibits the DNA binding activities of NF-κB, c-Fos, and c-Jun |
[79] | |
| A549 | ND | FIS enhances chemotherapeutic effect of Cisplatin FIS reverses Cisplatin-resistance of cells through MAPK/Survivin/Caspase pathways |
[99] | |
| Swiss albino mice | ND | FIS is a very successful drug in combating the mitochondrial dysfunction in an experimental model of lung carcinogenesis | [100] | |
| Swiss albino mice | ND | FIS significantly reduces the degree of histological lesions FIS restores the levels of lipid peroxidation (LPO), enzymic and nonenzymic antioxidants |
[101] | |
| Melanoma | WM35 | ND | FIS inhibits YB-1 in mutant BRAF melanoma cells FIS binds to RSK and suppresses its kinase activity FIS induces modulation of YB-1/RSK signaling FIS suppresses YB-1/RSK signaling independent of its effect on ERK FIS reduces MDR1 levels |
[102] |
| A375 | ND | |||
| M17 | ≈60 * | FIS decreases cells viability FIS induces apoptosis through the intrinsic pathway FIS damages MTP in uveal melanoma cells FIS increases the release of cytochrome c in cytosol FIS increases caspase-9 and -3 activities |
[83] | |
| SP6.5 | ≈85 * | |||
| A375 | ND | FIS reduces human melanoma cell invasion by inhibiting EMT FIS inhibits cell proliferation and tumor growth by downregulating the PI3K pathway |
[103] | |
| A375, RPMI-7951 |
ND | FIS treatment inhibits PI3K signaling pathway in melanoma cells FIS enhances sorafenib-mediated cleavage of caspase-3 and PARP FIS modulates expression of Bcl2 family proteins in BRAF-mutated melanoma cells FIS with sorafenib effectively down-regulates MAPK and PI3K signaling pathways FIS potentiates the sorafenib-mediated tumor growth inhibition in athymic nude mice |
[104] | |
| A375, RPMI-7951, Hs294T |
ND | FIS reduces invasion of melanoma cells FIS inhibits invasion of melanoma cells in three-dimensional human skin equivalents FIS inhibits melanoma cell invasion by targeting MEK1/2 and NFκB FIS inhibits phoshorylation of MEK1/2 and ERK1/2 FIS inhibits nuclear translocation of NFκB |
[86] | |
| Mel 928 | ND | FIS decreases the viability of 451Lu cells FIS induces G1-phase arrest in 451Lu cells FIS downregulates of Wnt protein and its coreceptors FIS decreases nuclear β-catenin levels FIS interferes with the functional cooperation between TCF-2 and β-catenin |
[85] | |
| WM35 | ND | |||
| 451Lu | 80 * ≈37 # ≈18 ^ |
|||
| Stomach | AGS | ≈45 * ≈13 # |
FIS decreases the viability FIS induces apoptosis |
[105] |
| SGC7901 | ND | FIS inhibits proliferation of gastric cancer cell and induces apoptosis FIS increases the proportion of cells at G2/M phase with simultaneous reduction in cells at S phase FIS increases caspase-7 activities FIS reduces the expression of Bcl2, Bcl-x and Bid FIS reduces of the activation of ERK 1/2 |
[106] | |
| AGS | ND | FIS inhibits cell proliferation, growth and viability FIS induces a G1 phase arrest in gastric cancer cells FIS increases the level of cyclin-dependent kinase inhibitor (CDKI) Cip1/p21 FIS induces apoptosis and mitochondrial membrane depolarization FIS causes upregulation of total p53 and its activation by phosphorylation at S15 position FIS increases the phosphorylation of gamma-H2A.X S139 in both the cell lines |
[107] | |
| SNU-1 | ND | |||
| Ovary | A2780 | ND | FIS reduces cell growth in both OC cell lines FIS induces apoptosis and necroptosis FIS-induced cell necroptosis involves the RIP3/MLKL pathway. |
[108] |
| VOCAR-3 | ND | |||
| A2780 | ND | FIS and CIS effectively inhibit proliferation of A2780 cells FIS induces nuclear fragmentation of A2780 cells |
[109] | |
| Pancreas | PANC-1 | ND | FIS promotes DSBs and inhibits HR repair in pancreatic cancer cells FIS regulates PHF10 expression via m6A RNA modification |
[110] |
| PANC-1 | ND | FIS dampens the proliferation of pancreatic cancer by downregulating Ki67 expression FIS triggers apoptosis of human pancreatic cancer cells FIS reduces the ability of infiltration and migration FIS dampens the expression of EMT-linked proteins FIS dampens the PI3K/AKT/mTOR axis FIS dampens pancreatic tumor growth of cell xenografts in nude mice |
[5] | |
| BxPC-3 | ≈120 * ≈75 # |
FIS inhibits the viability of human pancreatic cancer cells FIS induces S phase and DNA damage in pancreatic cancer cells FIS inhibits cell proliferation and induces DNA damage FIS upregulates of expression of RFXAP and other DNA-damage response genes FIS induces DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation |
[111] | |
| MiaPACA-2 | ND | |||
| PANC-1 | ≈400 * ≈200 # |
|||
| HPC-Y5 | ND | |||
| PANC-1 | ≈350 * ≈300 # |
FIS inhibits the viability of human pancreatic cancer cells FIS induces apoptosis and autophagy FIS stimulates the AMPK pathway FIS induces ER stress |
[112] | |
| BxPC-3 | ND | |||
| AsPC-1 | >100 * ≈40 # |
FIS induces apoptosis FIS inhibits invasion of chemoresistant PaC AsPC-1 cells through suppression of DR3 mediated NF-κB activation |
[113] | |
| Prostate | PrEC | ND | FIS and cabazitaxel significantly suppresses colony formation FIS increases cleavage of PARP FIS increases the level of Bax FIS decreases the level of Mcl-1 |
[114] |
| 22Rν1 | ND | |||
| C4-2 | ND | |||
| LNCaP, PC3 DU145 |
ND | FIS sensitizes the TRAIL-resistant androgen-dependent LNCaP cancer cells FIS augments TRAIL-mediated cytotoxicity and apoptosis in prostate cancer LNCaP cells FIS increases the expression of TRAIL-R1 FIS decreases the activity of NF-κB |
[115] | |
| PC3, DU145 LNCaP | ND | FIS induces growth inhibition of PC3 cells FIS decreases the activity of mTOR kinase FIS inhibits phosphorylation of mTOR FIS inhibits expression of the mTORC1 and mTORC2 constituents FIS inhibits formation of mTORC1/2 FIS inhibits activation of Akt FIS activates mTOR inhibitor tuberous sclerosis complex 2 |
[116] | |
| PC-3 | ND | FIS inhibits the adhesion, invasion, and migration in PC-3 cells FIS inhibits the expressions of MMP-2 and MMP-9 FIS inhibits the phosphorylation of JNK and Akt in PC-3 cells FIS inhibits the DNA binding activities of NF-κB, c-Fos and c-Jun |
[117] |
ND—not determined due the results obtained; *—IC50 values at 24 h; #—IC50 values at 48 h; ^—IC50 values at 72 h.