One of the important leading cause of death in the worldwide is cancer, followed by heart disease. Each year, the numbers of new patients with various cancers as well as the death rate from different types of malignancies both increased. Therefore, development of novel and effective therapeutic approaches is required to management of cancer progression, improvement of clinical manifections, and effective treatment of this disorder (1).

Among the various types of malignancies, blood, prostate, and lung cancers have been identified as the most prevalent forms of tumors with the highest incidence and death worldwide, particularly in the United States (US) (2). Blood cancers including leukemia, lymphoma, and myeloma account for approximately 10% of all diagnosed tumors with about 5 years survival rate. Blood cancers have effect on function and production of blood cells. There are numerous different methods for treating blood malignancies. Hematological malignancies are mostly treated with chemotherapy and systemic anti-cancer medications. However, the survival rate of patients with various blood malignancies is low due to the ineffectiveness of current medications and the high likelihood of relapse after treatment (2, 3). Therefore, identification of more comprehensive and functional treatments will be given more attention.

With significantly varying incidence and mortality data, lung cancer has also been highlighted as the primary reason for cancer-related deaths worldwide (4). In 2022 nearly 350 deaths per day were reported in the US from this solid tumor. Lung cancer affects over 2.8 million people worldwide (2, 5). Lung cancer and breast cancer account for about one-third of all diagnosed cases in female. Two important subtypes of this tumor are small cell lung cancer and non-small cell lung cancer. Depending on type and stage of the disease at the time of diagnosis, lung cancer patients treated with various approaches including immunotherapy, chemotherapy, and surgery. These treatments improved the relative survival rates of patients over time. However, two years survival rates estimated for lung cancer patients. Early detection and improvement of therapeutic approaches could significantly reduce lung cancer mortality (4, 6).

Prostate cancer is the leading cause of death among men (7). Also, it is the second most common cause of cancer-related death in the US, after lung cancer (8). The disease mainly affects on older men with an average age of about 66 years. Abnormal division of prostate cells and abnormal growth of the prostate lead to this disease. Similar to other cancers, treatment methods on prostate cancer treatment revealed many side effects. Given that increase the incidence rate of men with prostate cancer, it is crucial to find new strategies for managing or treating of this disease. Today, some dietary recommendations have been made to treat various conditions like cancer, such as nutrition and leading a better lifestyle, but the results and advice are not yet useful (9, 10).

Fruits and vegetables include the flavonoid subgroup of flavanols known as quercetin (Que; 3,5,7,3,4’-pentahydroxy flavonoids). This substance has numerous biological effects including anti-inflammatory, anti-cancer, and antioxidant effects. In addition, it revealed anti-cancer effects on cancer cells by regulating a number of molecular factors involved in signaling pathways, such as PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK1. Quercetin increases apoptosis and autophagy in cancer by activating caspase-3, inhibiting the phosphorylation of Akt, mTOR, and ERK, lessening β-catenin, and stabilizing the stabilization of HIF-1α. In addition, by reducing MMP and VEGF secretion, it inhibits cancer cell metastasis. Additionally, this compound leads to cancer cells apoptosis by decreasing bioenergy and targeting mitochondria (11).

The antitumor efficacy of quercetin derivatives varied from quercetin based on the subunit location and chain length. Insertion of Phenolic hydroxyl group such as etherification (O-alkylation) cancer cell proliferation may effectively suppressed. Modified quercetin properties vary in different cancer cell lines and additional researches is required to identify modified quercetin properties (12–14). Additionally, several nanoparticles placed onto the surface of the quercetin, including chemotherapeutic medicines like mitoxantrone (MTX) and adriamycin (ADR). This modified quercetin may reduce chemotherapeutic medication side effects and multi-drug resistance while enhancing synergistic anticancer benefits (15).

Regarding that blood, lung, and prostate cancers accounting for almost one-half of all diagnosed cases with tumor as well as different reports of therapeutic effects of quercetin in cancer studies, this study aimed to collect information and review all measures taken. Therefore, by recognizing the gaps in essays related to this drug and providing suggestions and solutions, it may be possible to use it more effectively to treat these cancers in the future.

Angiogenesis, which produces all capillaries, is regulated by a number of substances, including endostatin, adhesion molecules, and growth factors. Angiogenesis is essential for the growth of reproductive systems and the repair of injuries. Dysregulated angiogenesis contributes to tumor growth and metastasis. The tumor angiogenesis depends greatly on interactions between tumor cells and endothelial cells. VEGF play an important role in the growth and survival of endothelial cells, which promotes cell proliferation, increases vascular permeability, extravasates plasma fibrin, deposits cellulose, and tumor angiogenesis (16).

Natural products are a key component of cancer prevention. Many phytochemicals could be used to develop antiangiogenic medications. Flavonoids are polyphenolic substances that are present in nearly all food plants and have antiviral, antibacterial, anti-inflammatory, and cytoprotective effects on several animal and human cell types. According to epidemiological studies, high consumption of flavonoids may reduce cancer risks (17).

Quercetin have revealed an anti-tumor effect by reducing development of blood vessels. In addition, this natural component decrease tumor growth through targeting VEGFR-2-mediated angiogenesis pathway and suppressing the downstream regulatory component AKT in prostate and breast malignancies. The potential of quercetin to inhibit angiogenesis in drug-resistant cells increases its effects on anti-cancer medicines (18).

Metastasis is known as a major cause of cancer progression (19). In this process, cancer cells escape from the attack of the immune system, separate from the primary tumor, and attack the surrounding tissues and distant organs through the blood and lymphatic circulation systems (20). Many neoplastic illnesses are associated with uncommon angiogenesis, which has a significant impact on the growth and metastasis of tumors (21). To date, a variety of therapy approaches have been used to inhibit metastasis. Quercetin can decrease the cancer metastasis by suppressing various molecular pathways and angiogenesis (22).

Tumor angiogenesis and metastasis are caused by the interaction of VEGF and VEGF receptor 2 (VEGFR2), as well as by signals that are released in response to this process (23, 24).

Epithelial to mesenchymal transition is another factor in the development of metastasis (EMT). This process is associated with increased expression of mesenchymal markers including N cadherin, vimentin, and snail and decreased expression of epithelial proteins such as E cadherin and MUC1 (25). According to a previous study, quercetin inhibited tumor growth in prostate cancer by targeting the angiogenic pathway which mediated by VEGFR-2 and as a result inhibiting the expression of the AKT/mTOR/ribosomal protein S6 kinase (P70S6K) regulatory factor (17). Another investigation reported the effects of quercetin on inhibition of EMT, angiogenesis, and invasiveness through the epidermal growth factor receptor (EGFR)/VEGFR-2-mediated pathway in breast cancer (26). Matrix metalloproteinases (MMPs) are mentioned as compounds that play a special role in cancer invasion and metastasis processes by destroying the components of extracellular matrix (ECM) (27) (19). MMP2 and MMP9 are two remarkable compounds in metastatic breast cancer (28–30). In addition, a study investigated the effect of quercetin on breast cancer cell lines (MDA-MB-231) and showed that after treatment with this flavonoid, the expression of these two proteinases decreased (19). In studies related to colorectal cancer and squamous cell carcinoma of the head and neck (HNSCC), the inhibitory effect of quercetin on the migration of tumor cells has been shown by regulating the expression of MMPs (31, 32). According to the results obtained from the laboratory studies, quercetin by inhibiting the Akt activation pathway dependent on Snail, diminishing the expression of N-cadherin, vimentin, and ADAM9 and raising the expression of E-cadherin and proteins related to MMPs significantly inhibited the invasion and metastasis of lung cancer cells (33). In an examination of pancreatic cancer, quercetin inhibited the EMT, reduced invasive and metastasis, and reversed IL-6-induced EMT and MMP expression by inhibiting STAT3 signaling (34). Besides, quercetin 3-O-glucoside inhibited EGFR signaling, resulting in the suppression of EGF-induced migration in pancreatic cancer cells (35).

Transforming growth factor-β (TGF-β), as an inducer of EMT plays a vital role in prostate cancer metastasis. According to the research of Meghna M. Baruah, quercetin prevented EMT caused by TGF-β by reducing the expression of TGF-β caused by vimentin and N-cadherin, Twist, Snail, and Slug and increasing the expression of E-cadherin in PC-3 cells. The result of this process was the control of prostate cancer metastasis by this flavonoid (36).

In metastasis and progression of melanoma, activation of c-Met receptor tyrosine kinase has an important role. Hepatocyte growth factor (HGF)-mediated activation of C-Met signaling has been proposed as a therapeutic aim for melanoma metastasis. A group of researchers stated that quercetin showed anti-metastatic activity in melanoma by inhibiting c-Met phosphorylation, reducing its homodimerization, and ultimately suppressing the HGF/c-Met signaling pathway (37).

p53 protein, as a tumor suppressor, plays an important role in preventing cancer by regulating the cell cycle, apoptosis, and DNA repair (38). In this regard, has been stated that quercetin induced cell cycle arrest and apoptosis in hepatocellular carcinoma cells (HCC) by stabilizing or inducing p53 (39). Another experiment exhibited that quercetin exerted an anti-proliferative role on HCC cells by lessening intracellular ROS independently of p53 expression (40).

Protein kinase C (PKC) and phosphatidyl 3-kinase (PI3K) also play an influential role in increasing cell proliferation and survival. In Akhilendra Kumar Maurya’s study, quercetin prevented the proliferation of cancer cells by increasing the expression of p53 and BAX in hepatocellular carcinoma (HepG2) cell lines through the reduction of PKC, PI3K, and cyclooxygenase (COX-2) (41). During a study on melanoma cells, A375, it has been found that quercetin can inhibit cell proliferation by regulating proteins of the Wnt/β-catenin signaling pathway, DVL2, β-catenin, cyclin D1, Cox2, and Axin2 (42). By examining the effect of quercetin on the cell cycle and growth of human gastric cancer cells, it was determined that this compound has led to the multiplicity of this type of cancer by inhibiting the cell cycle in the G1 phase (43).

In many studies, the properties of quercetin, such as anti-inflammatory, anti-carcinogenic, and growth-suppressing effects, were analyzed in various cell lines of different cancers (76). Studies on the impact of combining quercetin with other compounds and drugs can be considered. He et al. Found that combining quercetin with dexamethasone promoted apoptosis in multiple myeloma cell lines (RPMI8226, ARP-1, and MM.1R). So, they had a synergistic effect on myeloma treatment. Also, in xenograft models, this combination enhances caspase-3 activity. However, the reduction of tumor burden didn’t differ in the quercetin combined with dexamethasone group compared to quercetin individually (71).

In combination with chloroquine (lysosome suppression), quercetin increases cell apoptosis (77).

The use of quercetin and chemotherapy can potentiate their effect on the malignant cell. Russo et al. Shown that CLL isolated-B cells treated with quercetin and anti CD95 increased cell death compared to a single treatment with quercetin or Anti CD-95. Furthermore, they reported quercetin improves the efficacy of Fludarabine which is used in CLL treatment, and suppresses cell growth through DNA synthesis disruption. Quercetin and Fludarabine can enhance apoptosis compared to monotherapy and reduce B-CLL cell resistance to Fludarabine (78, 79). In other studies, Li et al. Reports suggest quercetin could boost the impact of rituximab (anti-CD20 antibody) on diffuse large cell lymphoma (DLBCL) cell lines. The results showed that quercetin combination with rituximab increased apoptosis and cell growth inhibition compared with rituximab mono treatment in WSU-DLCL2 and Sudhl4 cell lines. Moreover, quercetin could potentiate the anti-tumor effect of rituximab through the STAT3 pathway. Treatment with combination agents further suppresses phosphorylated STAT3 and decreases the expression of genes associated with survival, such as Mcl-1 and Bcl-xl (80).

Vincristine (VCR) is an anti-neoplastic agent in NHL treatment. Zhu et al. Investigated the effect of Quercetin and VCR that were loaded on lipid-polymeric nanocarriers (LPNs). Que/VCR LPNs had a synergistic effect and decreased cell viability in Raji cells (a human Burkitt’s lymphoma cell line). So, quercetin increased the cytotoxicity of VCR. Also, they injected Raji cells into BALB/c mice to develop a tumor and then used Que/VCR LPN and Que/VCR solution. They found that tumor growth and tumor size decreased after treatment with two forms, Que/VCR, compared to a single therapy, and Que/VCR LPN had better efficacy than Que/VCR solution (81).

In combination with hyperthermia, Shen et al. Quercetin is a method used in cancer treatment by heating, and it was found to reduce Doxorubicin hydrochloride resistance in leukemia cell line K562 (82). So, quercetin may sensitize malignant cells to chemotherapy agents and potentiate their impacts. This capability needs to be further investigated.

For polyphenols, a class of natural compounds, treatment with ellagic acid, luteolin, and curcumin alone showed excellent anticancer effects. However, combined with quercetin, some adverse effects were observed, such as ROS increase, apoptosis promotion, and proliferation reduction. Mertens-Talcott et al. Observed that quercetin interaction with ellagic acid-induced synergistic effect led to cell cycle disturbance, apoptosis promotion, and proliferation reduction in the MOLT-4 human leukemia cell line (83–85).

Luteolin is another polyphenol flavonoid with anti-inflammatory and anti-cancer properties. In CLL cell lines HG-3 and EHEB, the cytotoxic impact of luteolin is enhanced in the presence of quercetin. The IC50 value of luteolin was decreased with increasing concentrations of quercetin (10, 20 and 30 M).

Curcumin is a natural anti-inflammatory and anti-tumor compound that is present in the spice turmeric (86). Studies showed that curcumin could suppress proliferation in CML cells. Altundag and colleagues found that the combination of quercetin and curcumin enhanced reactive oxygen species (ROS) generation compared to curcumin treatment alone in the CML cell line. Also, they found that co-treatment with quercetin and curcumin led to a reduction of mitochondrial membrane integrity, promotion of cytochrome C release, and apoptosis induction in CML cells (87). The combination of these two compounds has a similar effect on other cancer cell lines. Srivastava et al. results showed that in a melanoma cell line (A375), quercetin combined with curcumin displayed a higher suppressor effect on cell proliferation through Wnt/β-catenin signaling and decline of BCL-2 and caspase 3/7 induction. In addition, these compounds exhibit synergistic anti-proliferative effects on colon, lung, and breast cancer cells (HCT116, A549).

Notch, Hedgehog (Hh), and Wnt signaling pathways have the potential capacity for the growth of malignant hematopoietic stem cell clones. Cell growth can be suppressed by inhibitors of these pathways. In combination with quercetin, a Wnt inhibitor, and *-secretase inhibitors (GSIs), these drugs can suppress growth synergistically and increase the decline of Notch1 in the DND-41 T-ALL cell line. Also, in combination with the Hh inhibitor cyclopamine, quercetin has an additive effect on suppressing leukemia cell growth (88).

Quercetin promoted the activity of bortezomib (proteasome inhibitor) in the Primary Effusion Lymphoma PEL cell line, which is an aggressive B cell lymphoma. Cotreatment of quercetin and bortezomib led to the decline of cell survival compared to monotherapy in BC3 and BCBL1 cell lines (62).

Many in vitro studies indicate that quercetin is anti-carcinogenic, which suggests that when combined with other drugs, quercetin might be an effective treatment for cancer patients. A summary of previous studies on the therapeutic effects of quercetin on various types of blood cancer is listed in Table 1 .

According to the anti-carcinogenic feature of quercetin in many in vitro studies, it seems quercetin combined with other drugs will be a potential choice in clinical trial studies in cancer patients. Summary of previous studies on the therapeutic effects of quercetin in various types of blood cancer listed in Table 1 .

A high global incidence rate and cancer-related deaths are associated with lung cancer, with 1.76 million deaths worldwide (91). In the United States, lung cancer has been reported as the most commonly diagnosed cancer, with an incidence rate of 71.3 and 52.3 per 100000 in men and women, respectively, in 2019 (92). The morphological and genetic features of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in lung carcinoma have been correlated (93). Flavonoids have shown ineffective treatment for various cancers, especially lung cancer, in some studies. Among phytochemicals, quercetin displays a vital role in cancer-related molecules such as apoptotic proteins, cycle-dependent kinases (CDKs), cyclins, matrix metalloproteinase (MMPs), and growth factors via signaling pathways (94). The purpose of this article is to summarize a number of studies that focus on the role of quercetin in human lung cancer treatment, diagnosis, and prognosis.

Quercetin combined with delivery carriers like polymers, liposomes, chitosan, and other drug carriers enhanced solubility, absorption, circulation time, and target specificity (107). Utilization of mesoporous silica nanoparticulate like SBA-15 was defined as drug delivery purpose. Saad Alkahtani et al. revealed that 10μM quercetin-loaded SBA-15 (Que-SBA-15) decreased p-AKT, PI3K, and increased mTOR, caspase 9, and cytochrome c versus control samples (113). Cheng-Hung Chuang et al. demonstrated that trichostatin A (TSA), a histone deacetylase inhibitor, could not induce an apoptotic pathway in H1299 cells significantly until 72h. In contrast, quercetin, in combination with TSA, elevated apoptosis after 48 and 72h by about 62% and 88%. Also, death receptor 5 (DR5) levels, which is well known to mediate apoptosis pathways, mRNA, and protein, by 60% and 77%, respectively. Moreover, dual particles enhanced caspase3/10 and p300 expression. Studies have shown that quercetin itself, combined with chemotherapy, increased apoptosis in cancer cells (111). Furthermore, Yonghong Wang et al. reported an effective first-line chemotherapeutic drug, Paclitaxel (PTX), used for NSCLC treatment. Flow cytometry showed quercetin could increase cell cytotoxicity of PTX, and a combination of quercetin and PTX promoted apoptosis. Furthermore, Akt and ERK phosphorylation had no effective treatment with PTX, while that was markedly inhibited by the combination of quercetin and PTX (111). Similarly, Seung Hyun Lee and colleagues reported cell viability after being treated with quercetin and gemcitabine together, along with various concentrations of gemcitabine. A noticeable reduction was shown at 0.01 μg/ml dose of gemcitabine in both A-549 and H460 cell lines compared with gemcitabine alone (all p<0.05). further, a marked increase in caspase-3 activity at 0.1 μg/ml doses of dual molecules was observed, and a maximum increase of that was detected, 5.8-fold at 10 μg/ml and 9.2-fold at 1 μg/ml in A-549 and H460 cells, respectively. Also, quercetin combined with gemcitabine resulted in a downregulation of HSP70 expression significantly related to apoptosis (111). Liposomes consist of amphiphilic lipid molecules and can carry and transport hydrophilic and hydrophobic therapeutic agents (107). Muhammad Kashif Riaz et al. found that T7 was identified as a cell-targeting peptide with a specific binding affinity for TFR, which overexpressed on the surface of cancer cells, especially in the A-549 cell lines. Exposed quercetin to various types of T7 surface-functionalized liposomes (T7 targeted liposomes) along with its effect on lung cancer reported by Muhammad Kashif Riaz et al. they mentioned that on liposome surface in A-549 cells, T7-QR-Lip enhanced cytotoxicity, induction of apoptosis, and S-phase cell-cycle arrest by increasing T7 peptide, which increased the ability of liposomes to penetrate lung cancer cells by targeting TFR, density compared with free quercetin and non-targeted quercetin liposomes (QR-Lip). In addition, higher concentrations of T7-QR-Lip showed significant cytotoxicity (3 fold) compared to free QR. Further, T7-QR-Lip increased the anti-cancer activity of QR and lifespan of mice (p<0.01) (112). In a partly similar study, quercetin in combination with copper salt can improve solubility and suitable for intravenous administration in liposomal formulations. Analyses revealed that the area under the curve (AUC) for quercetin -copper in liposomes was 8382 μg h/ml, while for quercetin along with CuG (as a control) in liposomes was 1577 μg h/ml that, related to the rate of quercetin release into plasma and circulation of liposomes in mice (114). It is worthwhile to mention that exposure of A-549 cells to quercetin along with PMX, PMX/DCK showed concentration-dependent cytotoxicity with synergistic reduction of cell viability after treatment with 10, 20 μg/mL quercetin (61.0% ± 2.51% and 53.4% ± 4.42%, respectively), and suppressed transitions of cell-cycle at G2/M, G1/S, and cyclin-dependent kinases. Next, a wound-healing assay showed a higher sensitivity with reductions in cell proliferation/migration in cells treated with PMX/DCK and quercetin (30.5% and 14.9%, respectively). Also, PMX combined with quercetin (2.53-fold) showed a significant increase in the intestinal membrane permeability compared with free PMX. Further, quercetin was incorporated into NE, which resulted in higher permeability through the artificial membrane and Caco-2 cell Monolayer (16.6 ± 0.621 and 8.46 ± 2.21, respectively) compared with quercetin in water and a combination of 0.3% CMC. In addition, after oral administration of PMX/DCK-QCN-NE in rats, the Cmax and AUC last were increased compared with oral quercetin in 0.3% CMC (22.0- and 23.9-fold, respectively). The anti-cancer effect in A549 cell-bearing mice after once-daily oral administration of PMX/DCK-QCN-NE showed an inhibition and reduction of tumor growth and tumor mass compared with the oral PMX/DCK-NE and control groups (115). Moreover, cell proliferation of A-549 cells in lung cancer depended on quercetin -mediated gold nanoclusters (Que-GNCs) in a dose-dependent manner and a time-reliant manner from 0-24h. MMT assay showed the cell proliferation at 100 μg/ml concentration of Que-GNCs, which resulted in potential cytotoxicity from irregular cytoplasm with rupture in the cell membrane to complete damage in the cellular structure inhibited, and elevation of dead cells in that cell line was observed. In addition, using Que-GNCs measured by immunofluorescent probe induced enhanced reactive oxygen species (ROS) and oxidative stress at their doses from 50 μg/ml and even higher doses of 100 and 150 μg/ml (111). Summary of previous studies on the therapeutic effects of quercetin in lung cancer are listed in Table 2 .

One of the most common cancers diagnosed in adult men is prostate cancer (PCA) (120), which is classified as malignant with faster-growing cells and benign with slow-growing cells (121). After lung cancer, PCA is the second leading reason for cancer-related death in the United States and impacts about 70% of patients over 65 worldwide (8). The therapeutic influences of quercetin in different cancers, including prostate cancer, have been evaluated through in vitro and in vivo trials (55, 122–124). So, it may prevent the onset of this type of cancer because it indirectly blocks the promoters of two essential genes in the pathogenesis of prostate cancer, including androgen receptor (AR) and prostate-specific antigen (PSA) (125).

Resveratrol has previously been shown to block key signaling tracks associated with tumor onset and progression (143–145). The pro-apoptotic effects of resveratrol on human PCA cells have been demonstrated. On the other hand, its antiproliferative effects against PCA cells may be mediated by modulation of the PI3K/AKT path and the BCL2 proteins group (146). Harper et al. showed that resveratrol suppresses the progression of PCA in a TRAMP (transgenic adenocarcinoma of the mouse prostate) model (147). Another group found that resveratrol suppresses PCa growth and induces apoptosis in the TRAP (Transgenic Rat of Prostate Adenocarcinoma) model (148). As mentioned, quercetin, like resveratrol, can inhibit PCA cells (131, 149, 150). To this end, Chandra K. Singh and colleagues stated that the combination of Que-resveratrol has notable anti-tumor effects on a PCA mouse sample because their preclinical data showed a considerable lessening in tumor size and weight group (131). Ki67 and proliferating cell nuclear antigen (PCNA) are biomarkers that have important roles in cell proliferation, rapid growth, and cell division. 4-hydroxynonenal (4HNE) is a biomarker of oxidative stress, while Survivin prevents programmed cell death (151). They found significant reductions in 4HNE in all three treatment groups, which may be due to the reduction of 4HNE oxidative damage in PCA. They also observed significant reductions in Ki67 and PCNA proliferation markers and cell survival markers in response to quercetin and/or resveratrol.

In all three treatment groups, compared to the control, there was a significant increase in the incision of both caspase-8 and -9, which indicates the involvement of external and internal apoptotic trails in the inhibition of this type of tumor. In addition, a significant decrease in BCL2 was observed in all treatment groups and with a further reduction in the group with the quercetin -resveratrol combined treatment. On the other hand, no significant difference in BAX was shown either at the protein or mRNA levels. Their results indicated that the blend of quercetin and resveratrol might regulate some essential genes and signaling pathways that are dysregulated in PCA and thus may help treat PCA (143).

2-Methoxy estradiol (2-ME), a biologically endogenous product of 17β-estradiol (E2), has been shown to play an anti-tumor role in many tumors (152). In prostate cancer, 2ME can inhibit both androgen-dependent androgen-independent cancer cells in vitro and in vivo. Nonetheless, 2ME has the disadvantage of limited biological access and rapid degradation. A combination of drugs with fewer side effects and higher anticancer effects than monotherapy was proposed (153–156). Guodong Wang investigated quercetin’s antiproliferative and apoptotic activity in combination with 2ME in both androgen-dependent LNCaP and androgen-independent PC3 prostate cancer cell lines. They showed synergistic antiproliferative and pro-apoptotic activity that raised the G2/M stage cell population and significantly reduced the Bcl2/BAX ratio. The mixture of quercetin and 2ME is a new clinically pertinent therapy regimen that may enhance the anti-tumor influence on prostate cancer and reduce the side effects of quercetin or 2ME alone (157). These researchers also treated nude male BALB/c mice with PC3 and LNCaP cell xenograft tumors via quercetin or 2ME and their blend for one month. They observed that PC3 and LNCaP xenograft transplant tumors were more petite in the quercetin or 2ME cure group than in the control. Their suppression was more noticeable in the quercetin and 2ME mixture groups due to enhanced induction of apoptosis, enhanced inhibition of the phosphatidylinositol 3 kinase (PI3K)/Akt path, and angiogenesis (158). Another group assessed the synergistic impact of quercetin and 2ME on PC3 cells. The data demonstrated that both quercetin and 2ME could impede PC3 cell proliferation time-dependent. Synergistically, these agents showed higher antiproliferative effects. The potential for PC3 cell migration after drug treatment was also evaluated separately and synergistically. The blended group has a more substantial anti-migratory effect than each drug group and emphasizes the interaction between quercetin and 2ME in exerting anti-tumor effects against PCA metastasis (159). One study examined the influences of quercetin and vitamin C therapy on factors that influence the growth, metastasis, and angiogenesis of prostate cancer. Their results showed that treating prostate cancer cells with quercetin or vitamin C lessened the expression of chemokine receptors CXCR4 and CXCR7, but their blend therapy had a better influence. In addition, their results showed that quercetin and vitamin C reduced the expression of integrin α4,α5, and β1, which have an essential role in the adhesion and metastasis of these cancer cells in DU145 PC3 cells. Therefore, the use of this drug combination has shown an increase in quercetin efficiency in treating prostate cancer (160).

Several researchers have studied the anticancer power of the combination of arctigenin (Arc) and quercetin in prostate cancer. Because Arc is a potent inhibitor of AR signaling in LAPC-4 prostate cancer cells, the combined effects of Arc and quercetin on proliferation, apoptosis, cell migration, and underlying mechanisms in both androgen-dependent prostate cancer cell lines (LNCaP and LAPC-4) have been reviewed. Finally, their results showed that the combination therapy of Arc and quercetin increased the inhibitory effect of this drug on the growth of androgen-dependent prostate cancer cells, which was associated with increased regulation of several signaling pathways, including the AR and PI3K/Akt pathways (161).

Interestingly, one study used a synthetic analog of fistin and quercetin flavanols called TMFol (3 ‘, 4’, 5’-trimethoxyflavonol) to evaluate the therapeutic effect of this substance in prostate cancer. This investigation assessed the impact of TMFol in some prostate cancer cell lines, including 22Rv1, TRAMP C2, PC-3, and LNCaP, and in nude mice with 22Rv1 or TRAMP-C2 tumors. They showed that TMFol inhibited cell growth in all explored prostate cancer cell lines more powerfully than fistin or quercetin alone. It also inhibited the growth of TRAMP C2 tumors in vivo, whereas either fistin and quercetin alone lacked such activity in this model. In addition, TMFol reduced the development of the 22Rv1 tumor in vivo. This group of researchers knew that the main reason for the effectiveness of this drug in both models was apoptosis. In vitro, however, apoptosis was induced only in TRAMP C2 cells affected by this drug (162).

Due to the expanded ability to proliferate, migrate, and advance the expression and secretion of the metalloproteinase 9 (MMP9) matrix, the Du145III cells have a high invasive capacity. So that Tsai PH et al. evaluated the influence of dietary flavonoids such as luteolin and quercetin on the invasive power of Du145III cells by activating the JNK pathway. They showed that these medicines suppressed the expression of highly invasive Du145III cell malignancies, vasculogenic mimicry (VM), the formation of anchorage-independent spheres, and specific cancer stem cell (CSC) markers. Also, because they targeted CSC cells and prevented the invasion of cancer cells, maybe there is an anti-angiogenic and anti-metastatic role in these compounds (163).

Another study evaluated the synergistic effect of metformin with quercetin on prostate cancer cells. It confirmed co-treat effects on inhibiting the growth, migration, and invasion of the PC-3 and LNCaP cells. In the combined treatment of these factors, they observed more apoptosis than in the one-factor treatment induced by caspase and Bcl-2 family components. They also documented that the use of this combination dramatically impeded the VEGF/Akt/PI3K path. In vivo in nude mice showed a synergistic effect of these compounds in inhibiting the growth of prostate cancer cells (164).

A study investigated combining quercetin with curcumin on demyelination and AR re-expression in CaP cell lines -free AR such as PC3 and DU145. Finally, it has been documented that the combination of these two drugs has a significant effect on DMNT control, associated with hypomethylation, recovery of mRNA and AR protein levels, and induction of apoptosis through mitochondrial depolarization of PC3 and DU145. The result was re-sensitization of androgen-resistant CaP cells to AR-mediated apoptosis (165).

It has previously been suggested that green tea and quercetin target cellular signaling pathways from onset to tumor progression (166, 167). Also, docetaxel (Doc) can be an ideal drug for treating metastatic and castration-resistant prostate cancer. In the research of Piwen Wang et al., the role of green tea and quercetin in sensitizing prostate cancer cells to Doc has been investigated in vitro, including LAPC-4-AI and PC-3. According to the researchers, the increase in a stoppage in the G2/M phase and the increase in apoptosis in LAPC-4-AI and PC-3 cells compared to Doc alone due to the use of drug combinations including quercetin, and Doc, epigallocatechin gallate (EGCG) had observed. Overall, these agents increased PI3K/Akt inhibition and signaling and transcriptional activator (Stat) 3 compared to Doc alone while reducing the expression of the multidrug-resistant protein (MRP1). In addition, combining EGCG and quercetin compared with Doc alone showed an increase in tumor cell permeability and cell proliferation inhibition in LAPC4AI and PC3 cells (168).

Over the ex-two decades, many advances in PCA screening, treatment, and monitoring have greatly improved the quality of life and survival after diagnosis. However, more than 20% of patients diagnosed with PCA are still resistant to the treatment (169).

Docetaxel is the first-line chemotherapeutic agent for metastatic prostate cancer. Nonetheless, the emergence of resistance diminishes its effectiveness and restrains its survival benefits. An investigator group documented that quercetin inverts docetaxel resistance in the docetaxel-resistant cells (LNCaP/R, PC3/R) on proliferation, colonization, migration, infiltration, and apoptosis functions. In other words, they found that combination therapy of these two drugs significantly blocked the PI3K/Akt trail and boosted apoptosis (170).

While doxorubicin is used to treat prostate cancer, there is a high rate of chemotherapy failure due to the development of prostate cancer cells’ resistance to doxorubicin. A group suggested that c-met is associated with drug resistance in prostate cancer. Furthermore, quercetin treatment was shown to inhibit c-met expression in PC3/R cells significantly. Subsequent inhibition of the PI3K/AKT signaling pathway downstream of c-met was also observed. In addition, combination treatment with quercetin inhibited the PI3K/AKT pathway, resulting in doxorubicin-induced mitochondrial dysfunction, ROS release, caspase 3/9 cleavage, and apoptosis in PC3/R cells. Overall, it has been shown that combination therapy with quercetin can invert doxorubicin resistance in prostate cancer cells by targeting the c-met/PI3K/AKT ways (171).

Paclitaxel (PTX) is a chemotherapeutic drug used to treat cancer, including prostate. PTX causes apoptosis by disrupting the dynamic equilibrium between soluble tubulin dimer and polymerized tubulin, inhibiting metaphase-to-late cell migration (172). What is more, several clinical studies have confirmed that PTX increases survival in these patients. On the other hand, PTX has many side influences and can cause acquired drug resistance after treatment, thereby hindering its clinical application as an anticancer drug (173). In this regard, a group of scientists mixed Quercetin and PTX to treat prostate cancer and assessed their anti-tumor effects in vitro and in vivo. In vitro studies explored cancer cell proliferation, apoptosis, cell cycle arrest, and ROS production after treating them with Quercetin and PTX. They also examined intracellular endoplasmic reticulum (ER) stress and the ability to migrate. They also analyzed the effects of this mixture therapy on PC3 mice with cancer and evaluated possible anticancer mechanisms by immunohistochemical staining of several related proteins. They also examined the impact of the mixture of these drugs on PC3 mice with cancer. They discovered that Que+PTX synergistically inhibits the growth of prostate cancer cells, induces cell cycle arrest in the G2/M phase, and induces cell apoptosis. Also, quercetin effectively causes intracellular ROS production and ER stress, and downregulation of hnRNPA1 may underlie the inhibition of cell migration (89).

Due to its poor water solubility and low bioavailability, the clinical use of quercetin has been impaired. A group of researchers investigated the therapeutic effect of new nano micelles loaded with QCT (M-QCTs) on refractory prostate cancer. They found that QCT was effectively encapsulated in micelles, increasing the drug’s solubility in water. However, their study showed that the semi-maximal inhibitory concentration value of M-QCT was much lower than that of free QCT. Therefore, MQCT was significantly more potent than free QCT in inhibiting the proliferation of human androgen-independent PC3 cells and inducing apoptosis. In addition, M-QCT showed a perfect anti-tumor efficacy and almost a 50% reduction in tumor growth rate in the PC3 xenograft mouse model. This may be due to increased MQCT accumulation at the tumor site due to improved permeability and retention (EPR). Their study showed that MQCT remarkably increased drug assembly at the tumor site and had excellent anti-tumor activity in this cancer. Therefore, this novel drug delivery system represents a suitable and practical therapeutic technique for clinical therapy (174). Summary of previous studies on the therapeutic effects of quercetin in prostate cancer are listed in Table 3 .

Quercetin constitutes the major bioflavonoid in the human diet. It exerts anti-inflammatory and chemopreventive effects. In addition, quercetin can improve cancer progression through various mechanisms including down regulation of mutant p53 proteins; G1 phase arrest; tyrosine kinase inhibition; and down regulation of cell survival, proliferative and anti-apoptotic proteins. The concept of quercetin as an anti-cancer compound is supported by preclinical studies. However, clinical studies that support these application are few and the results are mixed.

Limitations and suggestions:

NL, ZY, MG, PK, BGh, MM, MhSh, PZB, and NE interpreted, and provided major contributions in writing the manuscript. All authors contributed to the article and approved the submitted version.