Table 2.

Anticancer effects of fisetin in different types of cancer.

Cancer	Outcome of the Study	Refs.
Prostate cancer	Fisetin is a potent HA synthesis inhibitor which increases the abundance of antiangiogenic HMM-HA and could be used for the management of prostate cancer.	[82]
	The treatment of cancer cells with fisetin showed a high expression of acetylated α-tubulin in a dose-dependent way.	[83]
	Fisetin sensitizes the tumor necrosis factor-related apoptosis-inducing ligand-resistant androgen-dependent LNCaP as well as the androgen-independent prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand-induced death.	[84]
	Fisetin acts as a dual inhibitor of mTORC1/2 signaling, leading to the induction of autophagic cell death and the inhibition of Cap-dependent translation in cancer cells.	[85]
Kidney cancer	Fisetin induced a sub-G1 population in a dose-dependent fashion and caused cell shrinkage and membrane blebbing. Cancer cells were highly sensitive, compared to normal cells, to fisetin treatment.	[38]
	Fisetin inhibited the migration and invasion of cancer cells via the downregulation of CTSS, metalloproteinase 9 and disintegrin.	[87]
Liver cancer	Fisetin inhibited autophagy via the activation of PI3K/Akt/mTOR and the modulation of the AMPK signaling pathways.	[89]
	Fisetin displayed a suggestively inhibitory role in cancer cell proliferation. Likewise, the death receptor 2 agonist of bromocriptine absolutely blocked cancer cell proliferation in a dose-dependent fashion.	[90]
Colon cancer	Fisetin dose-dependently blocked both DNA synthesis and cell growth and disturbed cell cycle progression.	[91]
	Fisetin treatment efficiently inhibited the cell viability and apoptosis of CPT11-LoVo cells compared to Oxaliplatin and parental LoVo cancer cells. Moreover, apoptosis was encouraged by fisetin treatment, endorsing Caspase-8 and Cytochrome-C expressions.	[92]
	Fisetin caused an increase in the levels of proapoptotic Bim and Bak and induced a reduction in the protein levels of antiapoptotic Bcl-2 and Bcl-xL.	[93]
	Securin reduction sensitizes human colon cancer cells to fisetin-induced apoptosis.	[94]
Gastric cancer	Fisetin substantially decreases G1 phase cyclins and CDKs levels, and the levels of p53 increased.	[95]
	Fisetin treatment with various concentrations suggestively decreased the proliferation rate of SGC7901 cells.	[96]
Pancreatic cancer	Combination treatment with gemcitabine and fisetin inhibited the proliferation of cancer cells and played role in the induction of apoptosis, as indicated by caspase 3/7 activation.	[97]
	PANC-1 cells were cultured with different concentrations of fisetin, and the findings exhibited that fisetin reduced PANC-1 cell viability in a dose- and time-dependent way.	[45]
	The transient downregulation of DR3 by RNA interference meaningfully increased fisetin-induced changes in cell proliferation, cell invasion and apoptosis.	[99]
Bile duct cancer	Fisetin caused the inhibition of the survival of cancer cells. It also encouraged cellular apoptosis additively in combination with gemcitabine.	[100]
Bladder cancer	Fisetin-induced apoptosis in bladder cancer is initiated through the regulation of two associated pathways: the downregulation of the NF-κB pathway and the upregulation of p53 activity.	[101]
	Fisetin inhibited the proliferation of EJ and T24 cells via blocking cell cycle progression in the G0/G1 phase and inducing apoptosis.	[51]
Lung cancer	Fisetin suppressed proliferation, adhesion, migration and invasion. The induction of apoptosis was noticed after fisetin treatment via decreasing the expression of cyclin-D and c-myc.	[103]
	Fisetin showed some protection against paclitaxel-mediated cytotoxicity.	[104]
	Fisetin efficiently enhanced the sensitivity of erlotinib-resistant cancer cells to erlotinib, possibly via inhibiting the abnormal enhancement of AKT as well as MAPK signaling pathways.	[106]
	Fisetin-treated cells demonstrated a dose-dependent prevention of the constituents of the mTOR signaling complex.	[56]
Skin cancer	Mice previously treated with fisetin binary ethosomes gel showed a noticeable decrease in the levels of the pro-inflammatory marker and a lower percentage of tumor incidences.	[109]
	Fisetin inhibited IKK activation, leading to a reduction in the enhancement of the Nuclear Factor-κB signaling pathway.	[71]
	The treatment of fisetin decreases cell proliferation markers and DNA damage, as demonstrated by the increased expression of p21 and p53 proteins.	[111]
Oral cancer	Fisetin induced cell death, G2/M phase arrest and the induction of apoptosis and decreased the level of mitochondria membrane potential.	[112]
	Fisetin induced apoptotic cell death via increased reactive oxygen species and Ca2+. Moreover, fisetin played a role in the increase in caspase-8, -9 and -3 activities as well as reduced the mitochondrial membrane potential.	[113]
	Fisetin expressively inhibits tumor cell proliferation and induces apoptosis in oral squamous cell carcinoma.	[114]
	Fisetin played a role in the inhibition of the enhancement of PI3K/AKT-controlled mTOR.	[54]
Leukemia	Fisetin was able to kill THP-1 cells in vivo, resulting in tumor shrinkage in the xenograft mouse model. Death induction in vitro was facilitated by an increase in the nitric, causing the activation of both the extrinsic and the intrinsic apoptotic pathways.	[117]
Breast cancer	Fisetin-induced apoptosis was revoked by z-VAD-fmk, a pan-caspase inhibitor. Additionally, the inhibition of autophagy by using fisetin was revealed as an extra route to speedy anticancer activity in MCF-7 cells.	[118]
	Fisetin suggestively decreased 2-O-tetradecanoylphorbol-13-acetate-caused cell invasion in breast cancer cells, and it was also found to inhibit the activation of the p38 MAPK.	[119]
	Fisetin inhibited breast cancer cells division and also played a role in the induction of apoptosis.	[120]
	Fisetin enhanced tumor cell apoptosis and decreased the growth of 4T1 cell-derived orthotopic breast tumors.	[57]
Ovarian cancer	Fisetin as well as fisetin nanoparticles showed an inhibitory effect on ovarian cancer cells in a dose-dependent way.	[122]
	In a rat model study, the tumor mass and tumor volume were meaningfully reduced under the effect of fisetin. A greater concentration of fisetin caused a substantial increase in Bax and a decrease in Bcl-2.	[123]
	Cell numbers were reduced after fisetin/fisetin micelles treatment in a time- and dose-dependent fashion.	[124]
Cervix cancer	Synergistic apoptosis was induced by the combination of fisetin and sorafenib in cancer cells.	[125]
	Fisetin induced the apoptosis of cervical cancer (HeLa) cells in a dose- and time-dependent fashion.	[126]
	SiHa cells treated with fisetin concentrations of 20 and 40 µM exhibited a decrease in motility of 46.0% and 81.3%, respectively, and similar findings were also seen in CaSki cells, with 62.1% and 90.2% of inhibition.	[127]
Endometrium cancer	Fisetin (20–100 µM) efficiently decreased the viability of KLE and Hec1 A cells and possibly changed the cell population at the G2/M stage.	[128]
Bone cancer	Fisetin suppressed migration, cell mobility and invasion and inhibited MMP-2 activity in U-2 OS cells.	[129]
	Fisetin was related to a reduction in colony formation in U2OS and Saos-2 cells, whereas it was not in MG-63 and MG-63 cells, and Saos-2 cells showed a reduced cell proliferation at concentrations of 40 and 20 µM of fisetin, respectively.	[130]
	The ERK1/2 and PI3K/Akt pathways were inhibited by fisetin, and fisetin enhanced the expressions of p-c-Jun, p-JNK and p-p38. Fisetin caused reactive oxygen species (ROS) generation as well as a reduction in mitochondrial membrane potential.	[131]
Brain cancer	Fisetin could be a possible therapeutic agent to counter human glioma cells based on its ability to activate ERK1/2 and to prevent the expression of ADAM9.	[132]
	Fisetin was found to have cytotoxicity at lower doses in T98G cells as compared to a positive control.	[133]
Retina cancer	Fisetin inhibited the migration and invasion of Y79 cells in a dose-dependent way.	[47]
Cancer of the lymphatic system	Fisetin (30 μM) treatment played role in the decreased protein expression of cIAP-2.	[135]
Thyroid cancer	Fisetin enhanced the expression of the caspase (-3, -8, and -9) and decreased the JAK 1 and STAT3 expression in cancer cells.	[63]