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Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach

King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65201, USA
Authors to whom correspondence should be addressed.
Those authors contributed equally to this manuscript.
Int. J. Mol. Sci. 2021, 22(22), 12455;
Submission received: 30 September 2021 / Revised: 2 November 2021 / Accepted: 13 November 2021 / Published: 18 November 2021


Cancer is, globally, one of the main causes of death. Even though various therapies are available, they are still painful because of their adverse side effects. Available treatments frequently fail due to unpromising responses, resistance to classical anticancer drugs, radiation therapy, chemotherapy, and low accessibility to tumor tissues. Developing novel strategies to minimize adverse side effects, improve chemotherapy sensitivity, and control cancer progression is needed. Many studies have suggested small dietary molecules as complementary treatments for cancer patients. Different components of herbal/edible plants, known as flavonoids, have recently garnered attention due to their broad biological properties (e.g., antioxidant, antiviral, antimicrobial, anti-inflammatory, anti-mutagenic, anticancer, hepatoprotective, and cardioprotective). These flavonoids have shown anticancer activity by affecting different signaling cascades. This article summarizes the key progress made in this area and discusses the role of flavonoids by specifically inhibiting the PI3K/Akt/mTOR pathway in various cancers.

1. Introduction

Cancer is a group of diseases where cells grow uncontrollably, and abnormal cells spread throughout the body via the bloodstream and the lymphatic system [1]. According to the World Health Organization (WHO), cancer was the second most lethal disease in 2019 [2]. Recently, a GLOBOCAN report estimated that there were approximately 10 million deaths due to cancer and 19.3 million new cases in 2020 [3]. Furthermore, a report published by WHO on 4 February 2020, warned that if the current upward trend in cancer incidences continues, the world will see a 60% rise in cancer cases in the next 20 years [2]. There are many reasons for the occurrence of cancer, but one possible cause is the aberrant regulation of different cell signaling pathways due to the acquisition of genetic and epigenetic changes [4]. One such pathway is the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR). Several studies have reported the inappropriate PI3K/Akt/mTOR pathway regulation in different cancers, such as breast, liver, colorectal, prostate, and gastric cancer [5,6,7]. Hence, the PI3K/Akt/mTOR pathway has become a “hot spot” of molecular biomarker-based/targeted therapy of different tumors.
Natural compounds obtained from plant sources have recently garnered interest due to their easy availability, non-toxic/low adverse effects, cost-effectiveness, and ability to modulate multiple pathways [8]. Among the natural compounds, flavonoids have gained attention as anticancer agents, and are documented as being effective against various types of cancer [9,10]. Flavonoids are of low-molecular-weight, comprising polyphenolic compounds, classified into six groups—isoflavonoids, flavanones, flavanols, flavonols, flavones, and anthocyanidins [11]. The primary source of these flavonoids is the regular human diet, including fruits, vegetables, grains, bark, roots, stems, flowers (Table 1 and Figure 1), plant-derived beverages, such as green tea, wine, and cocoa-based products [12,13,14,15,16,17,18,19,20]. Flavonoids have shown various activities, such as inhibiting cell proliferation and angiogenesis, cell cycle arrest, induction in apoptosis, and reversion in multidrug resistance [21,22]. Furthermore, it has also been reported to act as a pro-oxidant in some cases, and may interact with other therapeutic agents during biotransformation [23]. Rapid metabolism, low solubility, and poor absorption in the gastrointestinal tract hinder the real pharmacological potential of dietary flavonoids [24].

2. The Implication of PI3K/Akt/mTOR Pathway in Cancer

The PI3K/Akt/mTOR pathway is one of the most deregulated signaling cascades involved in the development of different human cancers. Each central node of this pathway is highly activated in most tumors [39,40]. The central nodes include phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), receptor tyrosine kinase (RTK) class I (Epidermal growth factor receptor; EGFR, human epidermal growth factor receptor 2; HER2, etc.), Akt, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). The PIK3CA gene encoding p110α catalytic subunit of PI3K is often mutated in most of cancer types [41,42]. Mutation in PIK3CA and independent activation of the PI3K pathway only (without Akt) can also induce cancer [43,44]. On the other hand, a mutation in the EGFR gene acts as an activator of PI3K and plays a role in the pathogenesis of non-small cell lung cancer [45]. Similarly, overexpression and amplification of the EGFR gene are frequently observed in glioblastoma [46]. Another member of the EGFR family, HER2, is overexpressed and amplified in invasive gastric and breast cancers. However, its overexpression is less frequently observed in other cancer types, such as ovarian, colon, salivary, biliary, and lung cancer [47]. The somatic mutations and amplification in pleckstrin homology (PH) domain (E17K) of Akt1 have been identified in various cancers, such as pancreatic, colorectal, and ovarian, and breast cancers [48]. The PI3K/Akt/mTOR pathway is a master regulator of cancer progression and is considered as one of the most important therapeutic targets. The PI3Ks phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), leading to Akt phosphorylation that affects the cancer cell growth, cell survival, and cell cycle [49,50]. At the same time, phosphatase, and tensin homolog (PTEN) act as antagonists of PI3K and dephosphorylate PIP3 into PIP2 [51,52]. The complete blockage of PI3K signaling might effectively control the progression of different types of cancer [50,53].
Akt plays an important role in regulating tumor-associated cell processes, including cell survival, growth, migration, cell cycle progression, angiogenesis, and epithelial-mesenchymal transition [54]. Inhibition of the Akt pathway induces apoptosis and inhibits Akt-associated tumor cell growth [55,56]. The activation of the Akt pathway takes place through different receptors, such as integrin receptors, cytokine receptors, B and T cell receptors, tyrosine kinases receptor, and G-protein-coupled receptors (GPCRs) (Figure 2) through PIP3 generated by PI3Ks [57,58]. PIP3 does not activate Akt directly but modifies Akt configuration by binding to its PH domain and recruit Akt to the plasma membrane allowing phosphoinositide-dependent kinase-1 (PDK1) to phosphorylate the kinase domain at Thr308 residue [59,60]. The activated Akt leads to the phosphorylation of different downstream proteins present in the nucleus, cytosol, plasma membrane, supporting cell growth and survival, among other cellular effects [61]. On the other hand, dephosphorylation of Akt at Thr308 and Ser473 residues, by protein phosphatase 2A (PP2A), leads to its inhibition [62], and could increase fibroblast proliferation, vasodilatation, inhibition of the forkhead box O1 (FOXO1) protein, cell cycle arrest, and activation of B-cell lymphoma 2 (Bcl-2) associated agonist of cell death (BAD), leading to increased cell survival, stimulation of mTOR, resulting in reduced apoptosis and autophagy, and increased translocation of glucose transporter type 4 (GLUT4) [63]. Several scientific reports suggested an aberrant Akt signaling pathway in different types of cancer, resulting in tumor aggressiveness in some cases. Abnormalities in Akt genes have been reported in various human cancers, such as gastric carcinoma, glioblastoma, and gliosarcoma, whereas Akt2 amplification has been reported in head and neck squamous cell carcinoma, pancreatic, ovarian, and breast cancers [64].
The mTOR pathway also plays a vital role in regulating different activities, such as cell survival, cell growth, metabolism, and protein synthesis in response to upstream signals [65]. This is a downstream substrate of PI3K and Akt with two distinct complexes mTORC1 and mTORC2 [66]. Akt activates mTOR activity either by direct phosphorylation of mTOR at Ser2448 or by indirect phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2). Direct phosphorylation of TSC2 at S939 and T1462 [67,68] by Akt releases its inhibitory effect on mTOR and upregulates mTOR activity. TSC2 makes a heterodimeric complex with TSC1 and acts as a negative regulator of GTPase-activating protein (GAP) activity [69]. Because TSC2 suppresses the activity of the Ras-related GTPase Rheb, a selective activator of mTORC1, inhibition of TSC2 by Akt results in activation of mTORC1 [70]. The hyperactivation of this cascade can stimulate tumor development and progression through different mechanisms such as promoting growth factor receptor signaling, suppression of autophagy, lipid metabolism, glycolytic metabolism, angiogenesis, and cancer cell migration [71,72]. The different growth factors, such as vascular endothelial growth factor, hepatocyte growth factor, transforming growth factor, platelet-derived growth factor, insulin-like growth factor 1, and epidermal growth factor regulate the activity of mTOR signaling [73].

3. Inhibition of PI3K/Akt/mTOR Signaling Pathway by Different Flavonoids

PI3K/Akt/mTOR signaling pathways are crucial to multiple aspects of cell growth and survival in physiological and pathological conditions, such as cancer [74]. In response to extracellular stimuli, the recruitment of class IA PI3K to the plasma membrane occurs by interaction of p85 and insulin receptor substrate (IRS) through the activation of RTKs or GPCRs [75]. The heterodimeric class IA PI3Ks phosphorylate PIP2 at position 3 of the inositol ring to convert it into PIP3, which acts as a second cellular messenger that controls cell growth, cell survival, and proliferation [76,77,78]. PIP3 binds to the PH domain of Akt and translocates it to the plasma membrane (Figure 3), where PDK-1 phosphorylates Akt [60,79]. Once Akt is activated, it further phosphorylates a broad array of proteins involved in cell cycle regulation, growth, proliferation, apoptosis, and cell survival [63,80]. The phosphatase PTEN plays a negative modulator of mTOR cascade [81]. It inhibits the signaling through the PI3K-Akt pathway through the involvement of TSC1/2 [82]. Deregulation of various components of the mTOR pathway, such as PI3K amplification/mutation, loss of PTEN function, overexpression of Akt, ribosomal protein S6 kinase beta-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), and overexpression of eukaryotic translation initiation factor 4E (eIF4E), has been reported in numerous cancers, especially melanoma, where variation in key elements of the mTOR signaling have major effects on tumor growth [83]. One study suggested natural compounds and herbs, such as resveratrol, diosgenin, timosaponin III, 3,3’-diindolylmethane, epigallocatechin gallate (EGCC), pomegranate, curcumin, gallic acid, and genistein, could directly or indirectly inhibit the mTOR pathway [84]. In the below-mentioned section, we have listed some well-known flavonoids reported as anticancer agents in various cancer models (Table 2).

3.1. Quercetin

Quercetin is a flavonol and is a subclass of flavonoids. Some vegetables and fruits, such as onions, scallions, kale, broccoli, apples, berries (and even teas), are the primary sources of quercetin [23]. Some studies reported that quercetin inhibits phosphorylation of the mTOR primary downstream targets, namely 4E-BP1 and ribosomal protein S6K [101,102,103]. It has shown a potential anticancer activity in various cancer cell lines and animal models in a dose-dependent manner. Quercetin has been reported to be more cytotoxic compared to ellagic acid and it inhibits cell cycle progression in the S phase in leukemia and breast cancer cells. It has also shown to have a ~5-fold increase in the life span of tumor-bearing mice than untreated mice [104].

3.2. Myricetin

Myricetin, a plant-derived flavonoid, commonly exists in fruits and other foods/beverages, such as oranges, berries, nuts, tea, red wine, and vegetables (tomatoes) [105], possessing anticancer effects [28,106]. It inhibits cell cycle progression and proliferation and induces apoptosis and autophagy in human colon cancer cells by inhibiting the PI3K/Akt/mTOR signaling [107]. Myricetin also suppresses breast cancer cell growth and inhibits UVB-induced skin cancer [108,109]. One study reported that myricetin induces apoptosis through ROS induction and inhibits cell migration, tube formation, and PI3K/Akt/mTOR signaling in human umbilical vascular endothelial cells [28].

3.3. Kaempferol

Kaempferol is a natural flavonol commonly found in plants and fruits, such as kale, beans, green tea, Brussels sprouts, spinach, apple, grapefruit, and broccoli [110]. It has been reported to have antioxidant and antitumor properties. Kaempferol exerts strong anticancer effects through inducing apoptosis, cell migration, cell cycle arrest at the G2/M phase, inhibiting and reducing the level of mTOR, pm-TOR, PI3K, p-PI3K, and Akt protein levels in the human malignant melanoma A375 cell line [29]. Further, it exerts anti-proliferative effects on lung cancer and human endothelial cells by activating mitogen-activated protein kinase (MAPK) signaling [111]. A recent study also suggested potent anticancer, anti-proliferation activity of kaempferol in liver cancer [112]. In addition, kaempferol has been reported to significantly inhibit HepG2 cell proliferation, invasion, and migration, and induce apoptosis by up/downregulating PTEN and microRNA-21 (miR-21), respectively, ultimately inhibiting the PI3K/Akt/mTOR pathway [85].

3.4. Isorhamnetin

Flavonoid isorhamnetin obtained from the medicinal plant Hippophae rhamnoides L. has shown anticancer effects in colorectal cancer. It has been reported to suppress cell proliferation and induce the G2/M phase cell cycle arrest by inhibiting the PI3K/Akt/mTOR pathway in colorectal and breast cancer [33,86].

3.5. Green Tea Catechins, Epicatechin, and Epigallocatechin-3-Gallate

Green tea catechin, such as epicatechin and epigallocatechin-3-gallate, is present in green tea, a typical refreshment drink enjoyed worldwide [113]. Epigallocatechin-3-gallate has shown significant anticancer activities in different cancer models [114]. Recent studies have suggested that epicatechin interacts and neutralizes reactive oxygen species (ROS) in the cell and modulates the MAP kinase pathway to inhibit cell proliferation [115]. In addition, it has shown inhibitory activities against Akt and NF-κB in combination with panaxadiol or cisplatin in HCT-116 and renal tubular carcinoma [116]. Some evidence shows that it downregulates doxorubicin-induced overexpression of P-glycoprotein through the inhibition of PI3K/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways [117,118]. Additionally, it downregulates the PI3K/Akt and MEK/ERK signaling pathways and promote apoptosis in T47D cells of human breast cancer [119,120].

3.6. Fisetin

Fisetin is a flavonol commonly found in some fruits/plants, such as strawberries, grapes, apples, persimmons, onions, kiwi, kale, etc. It shares antioxidant properties with many other plant polyphenols [121]. A study reported that a dietary tetrahydroxyflavone, fisetin inhibited human non-small cell lung cancer cells by downregulating the PI3K/Akt/mTOR signaling pathway [122]. Fisetin has shown to downregulate the PTEN protein levels in multiple myeloma U266 cells and A549 lung carcinoma [122,123]. In addition, it reduces phosphorylation of Akt, mTOR, microphthalmia-associated transcription factor (MITF), and p70S6K proteins in human melanoma 451Lu cells in a dose-dependent manner [122,124].

3.7. Lupiwighteone

Isoflavone, lupiwighteone is majorly present in medicinal plants Glycyrrhiza glabra, Lupinus sp., and Lotus pedunculatus. Lupiwighteone has shown anticancer activity in various cancer cells of neuroblastoma, prostate, and breast cancer [91,92]. It could also induce caspase-dependent and independent apoptosis in breast cancer cells by inhibiting the PI3K/Akt/mTOR pathway [92].

3.8. Apigenin

Flavone, apigenin is an active plant-originated compound found in parsley, celery, and chamomile. It has shown to inhibit cancer progression and development by blocking inhibitory-κB kinase (IKK) alpha activation and the PI3K/Akt/FoxO pathway in a TRAMP mice model [125,126]. It also inhibits cell proliferation and induces autophagy by blocking the PI3K/Akt/mTOR pathway in liver cancer cells [127].

3.9. Nobiletin

Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) is a polymethoxy flavonoid compound derived from citrus fruits [128]. It has shown several pharmacological activities, including anti-oxidative, anti-inflammatory, anticancer, cardio/neuro-protective, and anti-metabolic [128,129]. It has been reported to inhibit ovarian cancer cell growth by inhibiting the secretion of the primary angiogenesis mediators, Akt, hypoxia-inducible factor 1-alpha (HIF-1α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF). Moreover, it does not affect the viability of normal ovarian epithelial cells at less than 40 µM [130].

3.10. Galangin

Galangin is a natural flavonoid obtained from honey and Alpinia officinarum Hance (Zingiberaceae), one of the Chinese herbal medicines. It has various beneficial properties, such as antidiabetic, anticancer, antiviral, and antimicrobial, and does not show any complications [131]. A study reported that galangin could inhibit the proliferation, migration, and invasion of the A498 cells of kidney cancer. Furthermore, it could also induce apoptosis and suppress the PI3K/Akt/mTOR signaling pathway [96].

3.11. Hesperidin

Hesperidin is a dietary flavanone widely distributed in citrus fruits, such as oranges, lemon, and lime. Data obtained from several in vitro and in vivo studies suggested a wide spectrum of biological properties associated with hesperidin, which include anti-carcinogenic, antioxidant, and anti-inflammatory [97]. Scientific evidence has indicated that hesperidin induces apoptosis and cell cycle arrest and inhibits cancer cell proliferation by interacting with various cellular targets [31]. Further, it inhibits tumor metastasis, angiogenesis, and chemoresistance [31]. One study reported that hesperidin treatment could induce apoptosis and trigger autophagy by inhibiting the aurora-a mediated PI3K/Akt/mTOR and glycogen synthase kinase 3 beta (GSK-3β) pathway in colon cancer mouse model [132].

3.12. Anthocyanins

Anthocyanins are a subclass of flavonoids widely distributed in fruits, such as cherries, berries, grapes, and vegetables, as glycosides, attached to different sugars [133]. Cyanidin is one of the members of the anthocyanin family, which is reported to inhibit cell migration and reverse oxaliplatin-induced EMT biomarker changes through inactivation of PI3K/Akt signaling in hepatocellular carcinoma [100]. Pelargonidin is another member of anthocyanins, and exerts an anticancer effect in human osteosarcoma cells. This anthocyanin’s family member induces autophagy, triggers the ROS induced reduction in mitochondrial membrane potential, and induces cell cycle arrest at the G2/M phase. It also inhibits the expression of p-PI3K and p-Akt in a dose-dependent manner [38].

3.13. Delphinidin

Delphinidin plays a vital role in preventing oxidative stress, inflammation, angiogenesis, metastasis, and carcinogenesis [134,135] in different cancers, such as breast [136], prostate [137], lungs [138], liver [139], colon [140], and fibrosarcoma [141] by regulating different cell signal transduction pathways. Delphinidin has shown anti-proliferative properties through inactivation of the PI3K/Akt and ERK1/2 MAPK signaling pathway in ovarian cancer cells [99]. The dose-dependent treatment of delphinidin reduce the SKOV3 cell proliferation by inhibiting the PI3K/Akt and ERK1/2 mitogen-activated protein kinase signaling pathway [99].

3.14. Sulforaphane

Sulforaphane is an isothiocyanate, commonly found in cruciferous vegetables. It also possesses anticancer properties and acts as an effective natural agent to modulate the PI3K/Akt signaling pathway. One study demonstrated that sulforaphane inhibits lung cancer cell growth by inhibiting Akt phosphorylation and reduces PTEN expression in lung cancer xenografts mice. Due to this property, sulforaphane could be considered as an important anticancer agent for lung cancer treatment [142].

4. Biodisponibility/Bioavailability of Flavonoids

It is well known that human beings have been consuming flavonoids since ancient times. In the modern world, these bioactive flavonoids are widely consumed as part of the diet or nutritional supplements [143,144]. However, low/limited biodisponibility has been an issue that significantly limits the clinical usage of these compounds as anticancer agents [145,146,147]. The poor bioavailability of these flavonoids is due to metabolism carried out by phase II enzymes, resulting in hydrophilic excretable conjugates. Failed or inefficient excretion of these metabolites could hurt overall cellular metabolism, leading to higher exposure to flavonoids [148,149]. To increase the biodisponibility of these flavonoids, the scientific community is focusing their research on limiting the metabolism or targeted delivery of these compounds. These approaches, if successfully implemented, could lead to potent utilization of flavonoids as anticancer agents.

5. Conclusions

The above-mentioned scientific literature indicates the role of different signaling pathways in the progression of various cancers. The PI3K/Akt/mTOR is a well-known “hot spot” target for anticancer compounds. Due to natural resources, cost-effectiveness, and ease of use, flavonoids are recommended as anticancer agents. However, even with significant pharmacological potential, they are not fully exploited clinically because of their inherent properties, such as limited bioavailability, rapid metabolism, untargeted delivery, cytotoxicity to normal cells, etc. To enhance their anticancer potential, the possible usage of a mixture of flavonoids has been suggested, considering the probability of affecting different signaling cascades simultaneously. The use of state-of-the-art techniques, including various nanotechnology-based approaches, is also recommended to reduce/nullify the above-listed drawbacks. Their use, alongside currently available chemotherapeutic drugs, could help with reducing required doses, ultimately resulting in fewer side effects.

Author Contributions

T.A.Z.: original draft preparation and reviewing. M.S.: conceptualization, original draft preparation, and writing. M.T.: reviewing and editing. S.T.: reviewing, editing, and supervision. All authors have read and agreed to the published version of the manuscript.


The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through project number IFPRP: 30-141-1442, and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare that they have no conflict of interest.


AktProtein kinase
BADBCL2 associated agonist of cell death
BCL2B-cell lymphoma 2
4EBP1Eukaryotic translation initiation factor 4E binding protein 1
EGCGEpigallocatechin gallate
EGFREpidermal growth factor receptor
eIF4EEukaryotic translation initiation factor 4E
ERKExtracellular signal-regulated kinase
GPCRsG-protein-coupled receptors
GSK-3βGlycogen synthase kinase 3 beta
GLUT4Glucose transporter type 4
HER2Human epidermal growth factor receptor 2
HIF-1αHypoxia-inducible factor 1-alpha
IKKInhibitory-κB kinase
MAPKMitogen-activated protein kinase
Mitogen-activated protein kinase kinase
Microphthalmia-associated transcription factor
Nuclear factor kappa-light-chain-enhancer of activated B cells
Nitric oxide
mTORmammalian target of rapamycin
PI3KPhosphoinositide 3-kinase
PHPleckstrin homology
PDK1Phosphoinositide-dependent kinase-1
p70S6K1p70 ribosomal S6 kinase 1
PIK3CAPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha
PP2AProtein phosphatase 2A
PTENPhosphatase and tensin homolog deleted on chromosome 10
RHEB GDPRas homolog enriched in brain GDP
RHEB GTPRas homolog enriched in brain GTP
ROSReactive oxygen species
RTKReceptor tyrosine kinase
S6k1Ribosomal protein S6 kinase beta-1
TSCTuberous sclerosis complex
VEGFVascular endothelial growth factor


  1. Paul, C.D.; Mistriotis, P.; Konstantopoulos, K. Cancer cell motility: Lessons from migration in confined spaces. Nat. Rev. Cancer 2017, 17, 131–140. [Google Scholar] [CrossRef] [Green Version]
  2. WHO. WHO Outlines Steps to Save 7 Million Lives from Cancer. Available online: (accessed on 4 February 2020).
  3. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  4. Butti, R.; Das, S.; Gunasekaran, V.P.; Yadav, A.S.; Kumar, D.; Kundu, G.C. Receptor tyrosine kinases (RTKs) in breast cancer: Signaling, therapeutic implications and challenges. Mol. Cancer 2018, 17, 34. [Google Scholar] [CrossRef] [Green Version]
  5. Wei, J.; Gou, Z.; Wen, Y.; Luo, Q.; Huang, Z. Marine compounds targeting the PI3K/Akt signaling pathway in cancer therapy. Biomed. Pharmacother. 2020, 129, 110484. [Google Scholar] [CrossRef]
  6. Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507. [Google Scholar] [CrossRef]
  7. Jiang, N.; Dai, Q.; Su, X.; Fu, J.; Feng, X.; Peng, J. Role of PI3K/AKT pathway in cancer: The framework of malignant behavior. Mol. Biol. Rep. 2020, 47, 4587–4629. [Google Scholar] [CrossRef]
  8. Almatroodi, S.A.; Alsahli, M.A.; Almatroudi, A.; Verma, A.K.; Aloliqi, A.; Allemailem, K.S.; Khan, A.A.; Rahmani, A.H. Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways. Molecules 2021, 26, 1315. [Google Scholar] [CrossRef]
  9. Abotaleb, M.; Samuel, S.M.; Varghese, E.; Varghese, S.; Kubatka, P.; Liskova, A.; Büsselberg, D. Flavonoids in Cancer and Apoptosis. Cancers 2018, 11, 28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Badar Ul Islam, n.; Khan, M.S.; Husain, F.M.; Rehman, M.T.; Alzughaibi, T.A.; Abuzenadah, A.M.; Urooj, M.; Kamal, M.A.; Tabrez, S. mTor Targeting by Different Flavonoids for Cancer Prevention. Curr. Med. Chem. 2020. [CrossRef]
  11. Patil, V.M.; Masand, N. Chapter 12—Anticancer Potential of Flavonoids: Chemistry, Biological Activities, and Future Perspectives. In Studies in Natural Products Chemistry; Attaur, R., Ed.; Elsevier: Amsterdam, The Netherlands, 2018; Volume 59, pp. 401–430. [Google Scholar]
  12. Kopustinskiene, D.M.; Jakstas, V.; Savickas, A.; Bernatoniene, J. Flavonoids as Anticancer Agents. Nutrients 2020, 12, 457. [Google Scholar] [CrossRef] [Green Version]
  13. Kozłowska, A.; Szostak-Węgierek, D. Flavonoids—Food Sources, Health Benefits, and Mechanisms Involved. In Bioactive Molecules in Food; Mérillon, J.-M., Ramawat, K.G., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 1–27. [Google Scholar]
  14. Baby, J.; Devan, A.R.; Kumar, A.R.; Gorantla, J.N.; Nair, B.; Aishwarya, T.S.; Nath, L.R. Cogent role of flavonoids as key orchestrators of chemoprevention of hepatocellular carcinoma: A review. J. Food Biochem. 2021, 45, e13761. [Google Scholar] [CrossRef]
  15. Qiao, D.; Li, Y.; Xing, J.; Sun, P.; Wang, Y.; Zhang, Y.; Chen, L.; Ren, X.; Lin, Z.; Jin, J.; et al. Baicalein inhibits PI3K/AKT signaling pathway and induces autophagy of MGC-803 cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2019, 35, 613–618. [Google Scholar] [PubMed]
  16. Tao, Y.; Zhan, S.; Wang, Y.; Zhou, G.; Liang, H.; Chen, X.; Shen, H. Baicalin, the major component of traditional Chinese medicine Scutellaria baicalensis induces colon cancer cell apoptosis through inhibition of oncomiRNAs. Sci. Rep. 2018, 8, 14477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Cheriet, T.; Ben-Bachir, B.; Thamri, O.; Seghiri, R.; Mancini, I. Isolation and Biological Properties of the Natural Flavonoids Pectolinarin and Pectolinarigenin—A Review. Antibiotics 2020, 9, 417. [Google Scholar] [CrossRef] [PubMed]
  18. Porras, G.; Bacsa, J.; Tang, H.; Quave, C.L. Characterization and Structural Analysis of Genkwanin, a Natural Product from Callicarpa americana. Crystals 2019, 9, 491. [Google Scholar] [CrossRef] [Green Version]
  19. Zhou, Y.; Tu, Y.; Zhou, Q.; Hua, A.; Geng, P.; Chen, F.; Han, A.; Liu, J.; Dai, D.; Wang, S.; et al. Evaluation of acacetin inhibition potential against cytochrome P450 in vitro and in vivo. Chem. Biol. Interact. 2020, 329, 109147. [Google Scholar] [CrossRef]
  20. Carneiro, R.C.V.; Ye, L.; Baek, N.; Teixeira, G.H.A.; O’Keefe, S.F. Vine tea (Ampelopsis grossedentata): A review of chemical composition, functional properties, and potential food applications. J. Funct. Foods 2021, 76, 104317. [Google Scholar] [CrossRef]
  21. Chahar, M.K.; Sharma, N.; Dobhal, M.P.; Joshi, Y.C. Flavonoids: A versatile source of anticancer drugs. Pharmacogn. Rev. 2011, 5, 1–12. [Google Scholar] [CrossRef] [Green Version]
  22. Jucá, M.M.; Cysne Filho, F.M.S.; de Almeida, J.C.; Mesquita, D.d.S.; Barriga, J.R.d.M.; Dias, K.C.F.; Barbosa, T.M.; Vasconcelos, L.C.; Leal, L.K.A.M.; Ribeiro, J.E.; et al. Flavonoids: Biological activities and therapeutic potential. Nat. Prod. Res. 2020, 34, 692–705. [Google Scholar] [CrossRef]
  23. Islam, B.u.; Suhail, M.; Khan, M.K.; Zughaibi, T.A.; Alserihi, R.F.; Zaidi, S.K.; Tabrez, S. Polyphenols as anticancer agents: Toxicological concern to healthy cells. Phytother. Res. 2021. [CrossRef]
  24. Khan, H.; Ullah, H.; Martorell, M.; Valdes, S.E.; Belwal, T.; Tejada, S.; Sureda, A.; Kamal, M.A. Flavonoids nanoparticles in cancer: Treatment, prevention and clinical prospects. Semin Cancer Biol. 2021, 69, 200–211. [Google Scholar] [CrossRef]
  25. Fraga, C.G.; Croft, K.D.; Kennedy, D.O.; Tomás-Barberán, F.A. The effects of polyphenols and other bioactives on human health. Food Funct. 2019, 10, 514–528. [Google Scholar] [CrossRef] [Green Version]
  26. Vásquez-Garzón, V.R.; Macias-Pérez, J.R.; Jiménez-García, M.N.; Villegas, V.; Fattel-Fazenta, S.; Villa-Treviño, S. The chemopreventive capacity of quercetin to induce programmed cell death in hepatocarcinogenesis. Toxicol. Pathol. 2013, 41, 857–865. [Google Scholar] [CrossRef] [Green Version]
  27. Ji, Y.; Li, L.; Ma, Y.-X.; Li, W.-T.; Li, L.; Zhu, H.-Z.; Wu, M.-H.; Zhou, J.-R. Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice. J. Nutr. Biochem. 2019, 69, 108–119. [Google Scholar] [CrossRef]
  28. Kim, G.D. Myricetin Inhibits Angiogenesis by Inducing Apoptosis and Suppressing PI3K/Akt/mTOR Signaling in Endothelial Cells. J. Cancer Prev. 2017, 22, 219–227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Yang, J.; Xiao, P.; Sun, J.; Guo, L. Anticancer effects of kaempferol in A375 human malignant melanoma cells are mediated via induction of apoptosis, cell cycle arrest, inhibition of cell migration and downregulation of m-TOR/PI3K/AKT pathway. J. BUON 2018, 23, 218–223. [Google Scholar]
  30. Zhu, F.; Xu, Y.; Pan, J.; Li, M.; Chen, F.; Xie, G. Epigallocatechin Gallate Protects against MNNG-Induced Precancerous Lesions of Gastric Carcinoma in Rats via PI3K/Akt/mTOR Pathway. Evid. Based Complement Alternat. Med. 2021, 2021, 8846813. [Google Scholar] [CrossRef] [PubMed]
  31. Aggarwal, V.; Tuli, H.S.; Thakral, F.; Singhal, P.; Aggarwal, D.; Srivastava, S.; Pandey, A.; Sak, K.; Varol, M.; Khan, M.A.; et al. Molecular mechanisms of action of hesperidin in cancer: Recent trends and advancements. Exp. Biol. Med. 2020, 245, 486–497. [Google Scholar] [CrossRef] [Green Version]
  32. Zheng, Y.-H.; Yin, L.-H.; Grahn, T.H.M.; Ye, A.-F.; Zhao, Y.-R.; Zhang, Q.-Y. Anticancer effects of baicalein on hepatocellular carcinoma cells. Phytother. Res. 2014, 28, 1342–1348. [Google Scholar] [CrossRef] [PubMed]
  33. Zhang, H.-W.; Hu, J.-J.; Fu, R.-Q.; Liu, X.; Zhang, Y.-H.; Li, J.; Liu, L.; Li, Y.-N.; Deng, Q.; Luo, Q.-S.; et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci. Rep. 2018, 8, 11255. [Google Scholar] [CrossRef]
  34. Wang, X.; Song, Z.-J.; He, X.; Zhang, R.-Q.; Zhang, C.-F.; Li, F.; Wang, C.-Z.; Yuan, C.-S. Antitumor and immunomodulatory activity of genkwanin on colorectal cancer in the APC(Min/+) mice. Int. Immunopharmacol. 2015, 29, 701–707. [Google Scholar] [CrossRef]
  35. Tuli, H.S.; Tuorkey, M.J.; Thakral, F.; Sak, K.; Kumar, M.; Sharma, A.K.; Sharma, U.; Jain, A.; Aggarwal, V.; Bishayee, A. Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances. Front. Pharmacol. 2019, 10, 1336. [Google Scholar] [CrossRef] [Green Version]
  36. Bijak, M. Silybin, a Major Bioactive Component of Milk Thistle (Silybum marianum L. Gaernt.)-Chemistry, Bioavailability, and Metabolism. Molecules 2017, 22, 1942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Khoo, H.E.; Azlan, A.; Tang, S.T.; Lim, S.M. Anthocyanidins and anthocyanins: Colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food Nutr. Res. 2017, 61, 1361779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Chen, Y.; Wang, S.; Geng, B.; Yi, Z. Pelargonidin induces antitumor effects in human osteosarcoma cells via autophagy induction, loss of mitochondrial membrane potential, G2/M cell cycle arrest and downregulation of PI3K/AKT signalling pathway. J. BUON 2018, 23, 735–740. [Google Scholar]
  39. Owusu-Brackett, N.; Shariati, M.; Meric-Bernstam, F. Role of PI3K/AKT/mTOR in Cancer Signaling. In Predictive Biomarkers in Oncology: Applications in Precision Medicine; Badve, S., Kumar, G.L., Eds.; Springer International Publishing: Cham, Switzerland, 2019; pp. 263–270. [Google Scholar]
  40. Popova, N.V.; Jücker, M. The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int. J. Mol. Sci. 2021, 22, 1743. [Google Scholar] [CrossRef] [PubMed]
  41. Alqahtani, A.; Ayesh, H.S.K.; Halawani, H. PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis. Cancers 2020, 12, 93. [Google Scholar] [CrossRef] [Green Version]
  42. German, S.; Aslam, H.M.; Saleem, S.; Raees, A.; Anum, T.; Alvi, A.A.; Haseeb, A. Carcinogenesis of PIK3CA. Hered. Cancer Clin. Pract. 2013, 11, 5. [Google Scholar] [CrossRef] [Green Version]
  43. Zhang, W.; Haines, B.B.; Efferson, C.; Zhu, J.; Ware, C.; Kunii, K.; Tammam, J.; Angagaw, M.; Hinton, M.C.; Keilhack, H.; et al. Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors. Transl. Oncol. 2012, 5, 422–429. [Google Scholar] [CrossRef] [Green Version]
  44. Bruhn, M.A.; Pearson, R.B.; Hannan, R.D.; Sheppard, K.E. AKT-independent PI3-K signaling in cancer—Emerging role for SGK3. Cancer Manag. Res. 2013, 5, 281–292. [Google Scholar] [CrossRef] [Green Version]
  45. Fang, W.; Huang, Y.; Gu, W.; Gan, J.; Wang, W.; Zhang, S.; Wang, K.; Zhan, J.; Yang, Y.; Huang, Y.; et al. PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy. Transl. Lung. Cancer Res. 2020, 9, 1258–1267. [Google Scholar] [CrossRef]
  46. Saadeh, F.S.; Mahfouz, R.; Assi, H.I. EGFR as a clinical marker in glioblastomas and other gliomas. Int. J. Biol. Markers 2018, 33, 22–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: Variations on a theme. Oncogene 2008, 27, 5497–5510. [Google Scholar] [CrossRef] [Green Version]
  48. Chen, Y.; Huang, L.; Dong, Y.; Tao, C.; Zhang, R.; Shao, H.; Shen, H. Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis. Front. Cell Dev. Biol. 2020, 8, 996. [Google Scholar] [CrossRef] [PubMed]
  49. Zhao, L.; Vogt, P.K. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA 2008, 105, 2652–2657. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Fruman, D.A.; Chiu, H.; Hopkins, B.D.; Bagrodia, S.; Cantley, L.C.; Abraham, R.T. The PI3K Pathway in Human Disease. Cell 2017, 170, 605–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 1998, 273, 13375–13378. [Google Scholar] [CrossRef] [Green Version]
  52. Rascio, F.; Spadaccino, F.; Rocchetti, M.T.; Castellano, G.; Stallone, G.; Netti, G.S.; Ranieri, E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers 2021, 13, 3949. [Google Scholar] [CrossRef] [PubMed]
  53. Yang, J.; Nie, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer 2019, 18, 26. [Google Scholar] [CrossRef] [Green Version]
  54. Hinz, N.; Jücker, M. Distinct functions of AKT isoforms in breast cancer: A comprehensive review. Cell Commun. Signal. 2019, 17, 154. [Google Scholar] [CrossRef] [Green Version]
  55. Cheng, J.Q.; Lindsley, C.W.; Cheng, G.Z.; Yang, H.; Nicosia, S.V. The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene 2005, 24, 7482–7492. [Google Scholar] [CrossRef] [Green Version]
  56. Xie, X.; Tang, B.; Zhou, J.; Gao, Q.; Zhang, P. Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine. Oncol. Rep. 2013, 30, 773–782. [Google Scholar] [CrossRef] [Green Version]
  57. Song, G.; Ouyang, G.; Bao, S. The activation of Akt/PKB signaling pathway and cell survival. J. Cell Mol. Med. 2005, 9, 59–71. [Google Scholar] [CrossRef] [PubMed]
  58. Sugiyama, M.G.; Fairn, G.D.; Antonescu, C.N. Akt-ing Up Just About Everywhere: Compartment-Specific Akt Activation and Function in Receptor Tyrosine Kinase Signaling. Front. Cell Dev. Biol. 2019, 7, 70. [Google Scholar] [CrossRef] [PubMed]
  59. Altomare, D.A.; Testa, J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005, 24, 7455–7464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Truebestein, L.; Hornegger, H.; Anrather, D.; Hartl, M.; Fleming, K.D.; Stariha, J.T.B.; Pardon, E.; Steyaert, J.; Burke, J.E.; Leonard, T.A. Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation. Proc. Natl. Acad. Sci. USA 2021, 118, e2101496118. [Google Scholar] [CrossRef] [PubMed]
  61. Georgescu, M.-M. PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control. Genes Cancer 2010, 1, 1170–1177. [Google Scholar] [CrossRef] [PubMed]
  62. Liao, Y.; Hung, M.-C. Physiological regulation of Akt activity and stability. Am. J. Transl. Res. 2010, 2, 19–42. [Google Scholar] [PubMed]
  63. Nitulescu, G.M.; Van De Venter, M.; Nitulescu, G.; Ungurianu, A.; Juzenas, P.; Peng, Q.; Olaru, O.T.; Grădinaru, D.; Tsatsakis, A.; Tsoukalas, D.; et al. The Akt pathway in oncology therapy and beyond (Review). Int. J. Oncol. 2018, 53, 2319–2331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Chalhoub, N.; Baker, S.J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 2009, 4, 127–150. [Google Scholar] [CrossRef] [Green Version]
  65. Tian, T.; Li, X.; Zhang, J. mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int. J. Mol. Sci. 2019, 20, 755. [Google Scholar] [CrossRef] [Green Version]
  66. Jhanwar-Uniyal, M.; Wainwright, J.V.; Mohan, A.L.; Tobias, M.E.; Murali, R.; Gandhi, C.D.; Schmidt, M.H. Diverse signaling mechanisms of mTOR complexes: MTORC1 and mTORC2 in forming a formidable relationship. Adv. Biol. Regul. 2019, 72, 51–62. [Google Scholar] [CrossRef]
  67. Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.-L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002, 4, 648–657. [Google Scholar] [CrossRef] [PubMed]
  68. Manning, B.D.; Tee, A.R.; Logsdon, M.N.; Blenis, J.; Cantley, L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 2002, 10, 151–162. [Google Scholar] [CrossRef]
  69. Fruman, D.; Limon, J. Akt and mTOR in B Cell Activation and Differentiation. Front. Immunol. 2012, 3, 228. [Google Scholar] [CrossRef] [Green Version]
  70. Carroll, B.; Maetzel, D.; Maddocks, O.D.K.; Otten, G.; Ratcliff, M.; Smith, G.R.; Dunlop, E.A.; Passos, J.F.; Davies, O.R.; Jaenisch, R.; et al. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 2016, 5, e11058. [Google Scholar] [CrossRef]
  71. Yin, Y.; Hua, H.; Li, M.; Liu, S.; Kong, Q.; Shao, T.; Wang, J.; Luo, Y.; Wang, Q.; Luo, T.; et al. mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Res. 2016, 26, 46–65. [Google Scholar] [CrossRef] [Green Version]
  72. Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Gomez-Pinillos, A.; Ferrari, A.C. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol. Oncol. Clin. N. Am. 2012, 26, 483–505. [Google Scholar] [CrossRef] [PubMed]
  74. Porta, C.; Paglino, C.; Mosca, A. Targeting PI3K/Akt/mTOR Signaling in Cancer. Front. Oncol. 2014, 4, 64. [Google Scholar] [CrossRef] [Green Version]
  75. Hemmings, B.A.; Restuccia, D.F. PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol. 2012, 4, a011189. [Google Scholar] [CrossRef] [Green Version]
  76. Rodon, J.; Dienstmann, R.; Serra, V.; Tabernero, J. Development of PI3K inhibitors: Lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 2013, 10, 143–153. [Google Scholar] [CrossRef]
  77. Mandal, K. Review of PIP2 in Cellular Signaling, Functions and Diseases. Int. J. Mol. Sci. 2020, 21, E8342. [Google Scholar] [CrossRef]
  78. Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489–501. [Google Scholar] [CrossRef]
  79. Alessi, D.R.; Deak, M.; Casamayor, A.; Caudwell, F.B.; Morrice, N.; Norman, D.G.; Gaffney, P.; Reese, C.B.; MacDougall, C.N.; Harbison, D.; et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): Structural and functional homology with the Drosophila DSTPK61 kinase. Curr. Biol. 1997, 7, 776–789. [Google Scholar] [CrossRef] [Green Version]
  80. Nicholson, K.M.; Anderson, N.G. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002, 14, 381–395. [Google Scholar] [CrossRef]
  81. Chen, C.-Y.; Chen, J.; He, L.; Stiles, B.L. PTEN: Tumor Suppressor and Metabolic Regulator. Front. Endocrinol. 2018, 9, 338. [Google Scholar] [CrossRef] [Green Version]
  82. Roudsari, N.M.; Lashgari, N.-A.; Momtaz, S.; Abaft, S.; Jamali, F.; Safaiepour, P.; Narimisa, K.; Jackson, G.; Bishayee, A.; Rezaei, N.; et al. Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention. Pharmaceutics 2021, 13, 1195. [Google Scholar] [CrossRef]
  83. Pópulo, H.; Lopes, J.M.; Soares, P. The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 2012, 13, 1886–1918. [Google Scholar] [CrossRef] [PubMed]
  84. Tan, H.K.; Moad, A.I.H.; Tan, M.L. The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals. Asian Pac. J. Cancer Prev. 2014, 15, 6463–6475. [Google Scholar] [CrossRef] [Green Version]
  85. Zhu, G.; Liu, X.; Li, H.; Yan, Y.; Hong, X.; Lin, Z. Kaempferol inhibits proliferation, migration, and invasion of liver cancer HepG2 cells by down-regulation of microRNA-21. Int. J. Immunopathol. Pharmacol. 2018, 32, 2058738418814341. [Google Scholar] [CrossRef] [Green Version]
  86. Li, C.; Yang, X.; Chen, C.; Cai, S.; Hu, J. Isorhamnetin suppresses colon cancer cell growth through the PI3K-Akt-mTOR pathway. Mol. Med. Rep. 2014, 9, 935–940. [Google Scholar] [CrossRef]
  87. Zhou, Y.; Liang, X.; Chang, H.; Shu, F.; Wu, Y.; Zhang, T.; Fu, Y.; Zhang, Q.; Zhu, J.-D.; Mi, M. Ampelopsin-induced autophagy protects breast cancer cells from apoptosis through Akt-mTOR pathway via endoplasmic reticulum stress. Cancer Sci. 2014, 105, 1279–1287. [Google Scholar] [CrossRef]
  88. Liu, S.; Wang, X.-J.; Liu, Y.; Cui, Y.-F. PI3K/AKT/mTOR signaling is involved in (-)-epigallocatechin-3-gallate-induced apoptosis of human pancreatic carcinoma cells. Am. J. Chin. Med. 2013, 41, 629–642. [Google Scholar] [CrossRef] [PubMed]
  89. Wang, S.-D.; Chen, B.-C.; Kao, S.-T.; Liu, C.-J.; Yeh, C.-C. Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. BMC Complement Altern. Med. 2014, 14, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Ma, Y.; Wang, J.; Liu, L.; Zhu, H.; Chen, X.; Pan, S.; Sun, X.; Jiang, H. Genistein potentiates the effect of arsenic trioxide against human hepatocellular carcinoma: Role of Akt and nuclear factor-κB. Cancer Lett. 2011, 301, 75–84. [Google Scholar] [CrossRef]
  91. Ren, J.; Huang, Q.; Xu, Y.; Yang, M.; Yang, J.; Hu, K. Isoflavone lupiwighteone induces cytotoxic, apoptotic, and antiangiogenic activities in DU-145 prostate cancer cells. Anticancer Drugs 2015, 26, 599–611. [Google Scholar] [CrossRef]
  92. Won, Y.-S.; Seo, K.-I. Lupiwighteone induces caspase-dependent and -independent apoptosis on human breast cancer cells via inhibiting PI3K/Akt/mTOR pathway. Food Chem. Toxicol. 2020, 135, 110863. [Google Scholar] [CrossRef] [PubMed]
  93. Zou, M.; Hu, C.; You, Q.; Zhang, A.; Wang, X.; Guo, Q. Oroxylin A induces autophagy in human malignant glioma cells via the mTOR-STAT3-Notch signaling pathway. Mol. Carcinog. 2015, 54, 1363–1375. [Google Scholar] [CrossRef] [PubMed]
  94. Zou, M.; Lu, N.; Hu, C.; Liu, W.; Sun, Y.; Wang, X.; You, Q.; Gu, C.; Xi, T.; Guo, Q. Beclin 1-mediated autophagy in hepatocellular carcinoma cells: Implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling. Cell Signal. 2012, 24, 1722–1732. [Google Scholar] [CrossRef]
  95. Lee, H.J.; Venkatarame Gowda Saralamma, V.; Kim, S.M.; Ha, S.E.; Raha, S.; Lee, W.S.; Kim, E.H.; Lee, S.J.; Heo, J.D.; Kim, G.S. Pectolinarigenin Induced Cell Cycle Arrest, Autophagy, and Apoptosis in Gastric Cancer Cell via PI3K/AKT/mTOR Signaling Pathway. Nutrients 2018, 10, 1043. [Google Scholar] [CrossRef] [Green Version]
  96. Zhu, Y.; Rao, Q.; Zhang, X.; Zhou, X. Galangin induced antitumor effects in human kidney tumor cells mediated via mitochondrial mediated apoptosis, inhibition of cell migration and invasion and targeting PI3K/AKT/mTOR signalling pathway. J. BUON 2018, 23, 795–799. [Google Scholar]
  97. Roohbakhsh, A.; Parhiz, H.; Soltani, F.; Rezaee, R.; Iranshahi, M. Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci. 2015, 124, 64–74. [Google Scholar] [CrossRef]
  98. García-Maceira, P.; Mateo, J. Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: Implications for anticancer therapy. Oncogene 2009, 28, 313–324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Lim, W.; Song, G. Inhibitory effects of delphinidin on the proliferation of ovarian cancer cells via PI3K/AKT and ERK 1/2 MAPK signal transduction. Oncol. Lett. 2017, 14, 810–818. [Google Scholar] [CrossRef] [Green Version]
  100. Li, X.; Zhang, Z.-S.; Zhang, X.-H.; Yang, S.-N.; Liu, D.; Diao, C.-R.; Wang, H.; Zheng, F.-P. Cyanidin inhibits EMT induced by oxaliplatin via targeting the PDK1-PI3K/Akt signaling pathway. Food Funct. 2019, 10, 592–601. [Google Scholar] [CrossRef]
  101. Bianchi, S.; Giovannini, L. Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators. Nutr. Cancer 2018, 70, 490–501. [Google Scholar] [CrossRef]
  102. Wang, K.; Liu, R.; Li, J.; Mao, J.; Lei, Y.; Wu, J.; Zeng, J.; Zhang, T.; Wu, H.; Chen, L.; et al. Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy 2011, 7, 966–978. [Google Scholar] [CrossRef] [Green Version]
  103. Klappan, A.K.; Hones, S.; Mylonas, I.; Brüning, A. Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity. Histochem. Cell Biol. 2012, 137, 25–36. [Google Scholar] [CrossRef] [PubMed]
  104. Srivastava, S.; Somasagara, R.R.; Hegde, M.; Nishana, M.; Tadi, S.K.; Srivastava, M.; Choudhary, B.; Raghavan, S.C. Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis. Sci. Rep. 2016, 6, 24049. [Google Scholar] [CrossRef] [Green Version]
  105. Ross, J.A.; Kasum, C.M. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu. Rev. Nutr. 2002, 22, 19–34. [Google Scholar] [CrossRef]
  106. López-Lázaro, M.; Willmore, E.; Austin, C.A. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat. Res. 2010, 696, 41–47. [Google Scholar] [CrossRef]
  107. Zhu, M.-L.; Zhang, P.-M.; Jiang, M.; Yu, S.-W.; Wang, L. Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells. BMC Complement Med. Ther. 2020, 20, 209. [Google Scholar] [CrossRef]
  108. Jung, S.K.; Lee, K.W.; Byun, S.; Kang, N.J.; Lim, S.H.; Heo, Y.-S.; Bode, A.M.; Bowden, G.T.; Lee, H.J.; Dong, Z. Myricetin suppresses UVB-induced skin cancer by targeting Fyn. Cancer Res. 2008, 68, 6021–6029. [Google Scholar] [CrossRef] [Green Version]
  109. Sajedi, N.; Homayoun, M.; Mohammadi, F.; Soleimani, M. Myricetin Exerts its Apoptotic Effects on MCF-7 Breast Cancer Cells through Evoking the BRCA1-GADD45 Pathway. Asian Pac. J. Cancer Prev. 2020, 21, 3461–3468. [Google Scholar] [CrossRef]
  110. Dabeek, W.M.; Marra, M.V. Dietary Quercetin and Kaempferol: Bioavailability and Potential Cardiovascular-Related Bioactivity in Humans. Nutrients 2019, 11, 2288. [Google Scholar] [CrossRef] [Green Version]
  111. Kim, G.D. Kaempferol Inhibits Angiogenesis by Suppressing HIF-1α and VEGFR2 Activation via ERK/p38 MAPK and PI3K/Akt/mTOR Signaling Pathways in Endothelial Cells. Prev. Nutr. Food Sci. 2017, 22, 320–326. [Google Scholar] [CrossRef] [Green Version]
  112. Sharma, N.; Biswas, S.; Al-Dayan, N.; Alhegaili, A.S.; Sarwat, M. Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma. Antioxidants 2021, 10, 1419. [Google Scholar] [CrossRef]
  113. Suhail, M.; Mohammad, T.; Naoshad, M.; Huma, N.; Abdul, H.; Torki, A.Z.; Mohammad, A.K.; Mohd, R. A Critical Transcription Factor NF-κB as a Cancer Therapeutic Target and its Inhibitors as Cancer Treatment Options. Curr. Med. Chem. 2021, 28, 4117–4132. [Google Scholar] [CrossRef]
  114. Chen, B.-H.; Hsieh, C.-H.; Tsai, S.-Y.; Wang, C.-Y.; Wang, C.-C. Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway. Sci. Rep. 2020, 10, 5163. [Google Scholar] [CrossRef] [Green Version]
  115. Bernatoniene, J.; Kopustinskiene, D.M. The Role of Catechins in Cellular Responses to Oxidative Stress. Molecules 2018, 23, 965. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Shay, J.; Elbaz, H.A.; Lee, I.; Zielske, S.P.; Malek, M.H.; Hüttemann, M. Molecular Mechanisms and Therapeutic Effects of (-)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration. Oxid. Med. Cell Longev. 2015, 2015, 181260. [Google Scholar] [CrossRef] [Green Version]
  117. Satonaka, H.; Ishida, K.; Takai, M.; Koide, R.; Shigemasa, R.; Ueyama, J.; Ishikawa, T.; Hayashi, K.; Goto, H.; Wakusawa, S. (-)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Through the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways. Anticancer Res. 2017, 37, 6071–6077. [Google Scholar] [CrossRef] [Green Version]
  118. Suhail, M.; Parveen, A.; Husain, A.; Rehan, M. Exploring Inhibitory Mechanisms of Green Tea Catechins as Inhibitors of a Cancer Therapeutic Target, Nuclear Factor-κB (NF-κB). Biosci. Biotechnol. Res. Asia 2019, 16, 715–723. [Google Scholar] [CrossRef]
  119. Wang, J.; Man, G.C.W.; Chan, T.H.; Kwong, J.; Wang, C.C. A prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer. Cancer Lett. 2018, 412, 10–20. [Google Scholar] [CrossRef]
  120. Moradzadeh, M.; Hosseini, A.; Erfanian, S.; Rezaei, H. Epigallocatechin-3-gallate promotes apoptosis in human breast cancer T47D cells through down-regulation of PI3K/AKT and Telomerase. Pharmacol. Rep. 2017, 69, 924–928. [Google Scholar] [CrossRef]
  121. Grynkiewicz, G.; Demchuk, O.M. New Perspectives for Fisetin. Front. Chem. 2019, 7, 697. [Google Scholar] [CrossRef] [PubMed]
  122. Khan, N.; Afaq, F.; Khusro, F.H.; Mustafa Adhami, V.; Suh, Y.; Mukhtar, H. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int. J. Cancer 2012, 130, 1695–1705. [Google Scholar] [CrossRef] [Green Version]
  123. Jang, K.Y.; Jeong, S.-J.; Kim, S.-H.; Jung, J.H.; Kim, J.-H.; Koh, W.; Chen, C.-Y.; Kim, S.-H. Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Lett. 2012, 319, 197–202. [Google Scholar] [CrossRef]
  124. Syed, D.N.; Afaq, F.; Maddodi, N.; Johnson, J.J.; Sarfaraz, S.; Ahmad, A.; Setaluri, V.; Mukhtar, H. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels. J. Investig. Dermatol. 2011, 131, 1291–1299. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Shukla, S.; Bhaskaran, N.; Babcook, M.A.; Fu, P.; Maclennan, G.T.; Gupta, S. Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis 2014, 35, 452–460. [Google Scholar] [CrossRef] [Green Version]
  126. Shukla, S.; Kanwal, R.; Shankar, E.; Datt, M.; Chance, M.R.; Fu, P.; MacLennan, G.T.; Gupta, S. Apigenin blocks IKKα activation and suppresses prostate cancer progression. Oncotarget 2015, 6, 31216–31232. [Google Scholar] [CrossRef]
  127. Yang, J.; Pi, C.; Wang, G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed. Pharmacother. 2018, 103, 699–707. [Google Scholar] [CrossRef]
  128. Goh, J.X.H.; Tan, L.T.-H.; Goh, J.K.; Chan, K.G.; Pusparajah, P.; Lee, L.-H.; Goh, B.-H. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers 2019, 11, E867. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Huang, H.; Li, L.; Shi, W.; Liu, H.; Yang, J.; Yuan, X.; Wu, L. The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo and In Vitro. Evid Based Complement Alternat. Med. 2016, 2016, 2918796. [Google Scholar] [CrossRef] [Green Version]
  130. Chen, J.; Chen, A.Y.; Huang, H.; Ye, X.; Rollyson, W.D.; Perry, H.E.; Brown, K.C.; Rojanasakul, Y.; Rankin, G.O.; Dasgupta, P.; et al. The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway. Int. J. Oncol. 2015, 46, 2629–2638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Aloud, A.A.; Chinnadurai, V.; Govindasamy, C.; Alsaif, M.A.; Al-Numair, K.S. Galangin, a dietary flavonoid, ameliorates hyperglycaemia and lipid abnormalities in rats with streptozotocin-induced hyperglycaemia. Pharm. Biol. 2018, 56, 302–308. [Google Scholar] [CrossRef]
  132. Saiprasad, G.; Chitra, P.; Manikandan, R.; Sudhandiran, G. Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis. Eur. J. Cancer 2014, 50, 2489–2507. [Google Scholar] [CrossRef]
  133. Diaconeasa, Z.; Știrbu, I.; Xiao, J.; Leopold, N.; Ayvaz, Z.; Danciu, C.; Ayvaz, H.; Stǎnilǎ, A.; Nistor, M.; Socaciu, C. Anthocyanins, Vibrant Color Pigments, and Their Role in Skin Cancer Prevention. Biomedicines 2020, 8, E336. [Google Scholar] [CrossRef]
  134. Lamy, S.; Lafleur, R.; Bédard, V.; Moghrabi, A.; Barrette, S.; Gingras, D.; Béliveau, R. Anthocyanidins inhibit migration of glioblastoma cells: Structure-activity relationship and involvement of the plasminolytic system. J. Cell Biochem. 2007, 100, 100–111. [Google Scholar] [CrossRef]
  135. Kim, M.-H.; Jeong, Y.-J.; Cho, H.-J.; Hoe, H.-S.; Park, K.-K.; Park, Y.-Y.; Choi, Y.H.; Kim, C.-H.; Chang, H.-W.; Park, Y.-J.; et al. Delphinidin inhibits angiogenesis through the suppression of HIF-1α and VEGF expression in A549 lung cancer cells. Oncol. Rep. 2017, 37, 777–784. [Google Scholar] [CrossRef]
  136. Ozbay, T.; Nahta, R. Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines. Breast Cancer 2011, 5, 143–154. [Google Scholar] [CrossRef]
  137. Ko, H.; Jeong, M.-H.; Jeon, H.; Sung, G.-J.; So, Y.; Kim, I.; Son, J.; Lee, S.-W.; Yoon, H.-G.; Choi, K.-C. Delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis, by inducing DR5 and causing caspase-mediated HDAC3 cleavage. Oncotarget 2015, 6, 9970–9984. [Google Scholar] [CrossRef]
  138. Pal, H.C.; Sharma, S.; Strickland, L.R.; Agarwal, J.; Athar, M.; Elmets, C.A.; Afaq, F. Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways. PLoS ONE 2013, 8, e77270. [Google Scholar] [CrossRef] [Green Version]
  139. Feng, R.; Wang, S.Y.; Shi, Y.-H.; Fan, J.; Yin, X.-M. Delphinidin induces necrosis in hepatocellular carcinoma cells in the presence of 3-methyladenine, an autophagy inhibitor. J. Agric. Food Chem. 2010, 58, 3957–3964. [Google Scholar] [CrossRef]
  140. Yun, J.-M.; Afaq, F.; Khan, N.; Mukhtar, H. Delphinidin, an anthocyanidin in pigmented fruits and vegetables, induces apoptosis and cell cycle arrest in human colon cancer HCT116 cells. Mol. Carcinog. 2009, 48, 260–270. [Google Scholar] [CrossRef] [Green Version]
  141. Filipiak, K.; Hidalgo, M.; Silvan, J.M.; Fabre, B.; Carbajo, R.J.; Pineda-Lucena, A.; Ramos, A.; de Pascual-Teresa, B.; de Pascual-Teresa, S. Dietary gallic acid and anthocyanin cytotoxicity on human fibrosarcoma HT1080 cells. A study on the mode of action. Food Funct. 2014, 5, 381–389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Yang, M.; Wang, H.; Zhou, M.; Liu, W.; Kuang, P.; Liang, H.; Yuan, Q. The natural compound sulforaphene, as a novel anticancer reagent, targeting PI3K-AKT signaling pathway in lung cancer. Oncotarget 2016, 7, 76656–76666. [Google Scholar] [CrossRef]
  143. Zduńczyk, Z.; Juśkiewicz, J.; Estrella, I. Cecal parameters of rats fed diets containing grapefruit polyphenols and inulin as single supplements or in a combination. Nutrition 2006, 22, 898–904. [Google Scholar] [CrossRef]
  144. Rodrigo, R.; Libuy, M.; Feliu, F.; Hasson, D. Polyphenols in disease: From diet to supplements. Curr. Pharm. Biotechnol. 2014, 15, 304–317. [Google Scholar] [CrossRef]
  145. Garcia-Oliveira, P.; Otero, P.; Pereira, A.G.; Chamorro, F.; Carpena, M.; Echave, J.; Fraga-Corral, M.; Simal-Gandara, J.; Prieto, M.A. Status and Challenges of Plant-Anticancer Compounds in Cancer Treatment. Pharmaceuticals 2021, 14, 157. [Google Scholar] [CrossRef]
  146. Amawi, H.; Ashby, C.R.; Tiwari, A.K. Cancer chemoprevention through dietary flavonoids: What’s limiting? Chin. J. Cancer 2017, 36, 50. [Google Scholar] [CrossRef] [Green Version]
  147. Hu, M.; Wu, B.; Liu, Z. Bioavailability of Polyphenols and Flavonoids in the Era of Precision Medicine. Mol. Pharm. 2017, 14, 2861–2863. [Google Scholar] [CrossRef] [Green Version]
  148. Wang, S.; Xing, H.; Zhao, M.; Lu, D.; Li, Z.; Dong, D.; Wu, B. Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport. Curr. Drug Metab. 2016, 17, 922–929. [Google Scholar] [CrossRef]
  149. Neri-Numa, I.A.; Cazarin, C.B.B.; Ruiz, A.L.T.G.; Paulino, B.N.; Molina, G.; Pastore, G.M. Targeting flavonoids on modulation of metabolic syndrome. J. Funct. Foods 2020, 73, 104132. [Google Scholar] [CrossRef]
Figure 1. Common flavonoids from dietary sources, with their biological activities. EGCG; Epigallocatechin gallate. (Source: The effects of polyphenols and other bioactives on human health. accessed on 29 October 2021).
Figure 1. Common flavonoids from dietary sources, with their biological activities. EGCG; Epigallocatechin gallate. (Source: The effects of polyphenols and other bioactives on human health. accessed on 29 October 2021).
Ijms 22 12455 g001
Figure 2. PI3K/Akt signaling pathway; PIP2, phosphatidylinositol 4, 5-bisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PDK1, 3-phosphoinositide-dependent kinase 1; PP2A, protein phosphatase 2A; BAD, BCL2 associated agonist of cell death; GLUT4, glucose transporter type 4; GPCRs, G-protein-coupled receptors; TSC, tuberous sclerosis complex; FOXO1, forkhead box O1 protein; NO, nitric oxide.
Figure 2. PI3K/Akt signaling pathway; PIP2, phosphatidylinositol 4, 5-bisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PDK1, 3-phosphoinositide-dependent kinase 1; PP2A, protein phosphatase 2A; BAD, BCL2 associated agonist of cell death; GLUT4, glucose transporter type 4; GPCRs, G-protein-coupled receptors; TSC, tuberous sclerosis complex; FOXO1, forkhead box O1 protein; NO, nitric oxide.
Ijms 22 12455 g002
Figure 3. mTOR signaling cascade; IGF-1, insulin-like growth factor 1; EGF, epidermal growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; PIP2, phosphatidylinositol 4, 5-bisphosphate; PDK1, 3-phosphoinositide-dependent kinase 1; TSC1/2, tuberous sclerosis complex 1/2; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; eIF4E, eukaryotic translation initiation factor 4E; PTEN, phosphatase and tensin homolog deleted on chromosome 10; IRS1, insulin receptor substrate 1; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; p70S6K1, p70 ribosomal S6 kinase 1; Rheb GDP, Ras homolog enriched in brain GDP; Rheb GTP, Ras homolog enriched in brain GTP.
Figure 3. mTOR signaling cascade; IGF-1, insulin-like growth factor 1; EGF, epidermal growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; PIP2, phosphatidylinositol 4, 5-bisphosphate; PDK1, 3-phosphoinositide-dependent kinase 1; TSC1/2, tuberous sclerosis complex 1/2; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; eIF4E, eukaryotic translation initiation factor 4E; PTEN, phosphatase and tensin homolog deleted on chromosome 10; IRS1, insulin receptor substrate 1; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; p70S6K1, p70 ribosomal S6 kinase 1; Rheb GDP, Ras homolog enriched in brain GDP; Rheb GTP, Ras homolog enriched in brain GTP.
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Table 1. Major dietary sources of different flavonoids inhibiting PI3K/Akt/mTOR pathway.
Table 1. Major dietary sources of different flavonoids inhibiting PI3K/Akt/mTOR pathway.
Class of FlavonoidsInhibitors of PI3K/Akt/mTORDietary SourcesReferences
FlavonolsQuercetin, myricetin, kaempferol, isorhamnetin, ampelopsinGreen tea, black tea, onion, apple
with peel, oranges, blueberries, raw spinach, kale, broccoli, almonds, walnuts, dark chocolate, white wine, and red wine
FlavanolEGCGGreen tea, black tea, cranberries, strawberries, red wine, almonds, hazelnuts, and dark chocolate[30]
FlavanonesHesperidin citrus fruit, oranges, lemon, and grapefruit[31]
FlavonesBaicalein, acacetin, genkwanin, oroxylin A, pectolinarigenin, galanginOrange, yellow fruits, spices, and vegetables[32,33,34]
IsoflavonesGenistein, lupiwighteoneSoy, tofu, legumes, Glycyrrhiza glabra, Lupinus, and Lotus pedunculatus[35]
FlavonolignanSilibininMilk thistle (Silybum marianum)[36]
AnthocyaninsDelphinidin, cyanidin, pelargonidinRed to purplish, blue-colored leafy vegetables, blueberries, other berries, currants, grapes, pomegranate, blue corn, grains, roots, tubers, and red wine[37,38]
Table 2. Different flavonoids and their PI3K/Akt/mTOR inhibitory activity.
Table 2. Different flavonoids and their PI3K/Akt/mTOR inhibitory activity.
Name of InhibitorStructure of InhibitorInhibitory ActivityCancer/Cell TypeReference
Quercetin Ijms 22 12455 i001Triggers apoptosis by stimulating autophagy, inhibits the Akt/mTOR pathway HCC[26,27]
Myricetin Ijms 22 12455 i002Suppresses angiogenesis by inducing apoptosis, inhibits the PI3K/Akt/mTOR pathwayEndothelial cells [28]
Kaempferol Ijms 22 12455 i003Induces apoptosis, cell cycle arrest at G2/M, inhibits cell migration, PI3k/Akt/mTOR downregulation Melanoma and liver cancer[29,85]
Isorhamnetin Ijms 22 12455 i004Cell cycle arrest at G2/M phase, inhibits cell proliferation by suppressing PI3K/Akt/mTOR pathwayColorectal and breast cancer[33,86]
Ampelopsin Ijms 22 12455 i005Induces apoptotic and autophagy through the Akt-mTOR pathway via ER stressMDA-MB-231 and MCF-7 breast cancer [87]
EGCG Ijms 22 12455 i006Suppresses the proliferation and induces apoptosis, downregulates the expression of pAkt and p-mTOR, inhibits the PI3K/Akt/mTOR Gastric carcinoma[30,88]
Genistein Ijms 22 12455 i007Suppresses Akt and the NF-κB pathway through different cascadesHCC[89,90]
Lupiwighteone Ijms 22 12455 i008Induces the antiangiogenic activities, triggers the caspase-dependent and independent apoptosis through PI3K/Akt/mTOR pathway inhibitionProstate and breast cancer [91,92]
Baicalein Ijms 22 12455 i009Deactivate PI3K/Akt pathwayHCC[32]
Acacetin Ijms 22 12455 i010Induces cell cycle arrest at G2/M phase, induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway Breast cancer [33]
Genkwanin Ijms 22 12455 i011Significantly inhibits cell proliferation, induces cell cycle arrest at G2/M phase, induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway Colorectal and breast cancer [33,34]
Oroxylin A Ijms 22 12455 i012Inhibits the proliferation by inducing autophagy and suppresses the Akt and ERK activation and the phosphorylation of mTOR and STAT3Glioma cells[93,94]
Pectolinarigenin Ijms 22 12455 i013Induces cell cycle arrest at G2/M phase, induces autophagic and apoptotic cell death through downregulation of PI3K/Akt/mTOR pathway Gastric cancer [95]
Galangin Ijms 22 12455 i014Inhibits the cell proliferation, migration and invasion, induces apoptosis, suppresses PI3K/Akt/mTOR signaling A498 cells[96]
Hesperidin Ijms 22 12455 i015Induces apoptosis and autophagy by inhibiting Aurora-A mediated PI3K/Akt/mTOR and GSK-3β pathways Colon cancer[31,97]
Silibinin Ijms 22 12455 i016Anti-proliferative, inhibits HIF-1α and the mTOR/p70S6K/4E-BP1 signaling pathway Hepatoma cells[36,98]
Delphinidin Ijms 22 12455 i017Inhibits cell proliferation by inactivating the PI3K/Akt, and ERK1/2 mitogen-activated protein pathwayOvarian cancer[99]
Cyanidin Ijms 22 12455 i018Inhibits cell migration and reverses drug resistance by suppressing the PI3K/Akt pathway HCC[100]
Pelargonidin Ijms 22 12455 i019Triggers autophagy and ROS-induced decline in MMP, cell cycle arrest at the G2/M phase through inhibiting PI3K and p-Akt signaling Human osteosarcoma[38]
HCC, hepatocellular carcinoma; MMP, mitochondrial membrane potential.
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Zughaibi, T.A.; Suhail, M.; Tarique, M.; Tabrez, S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach. Int. J. Mol. Sci. 2021, 22, 12455.

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Zughaibi TA, Suhail M, Tarique M, Tabrez S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach. International Journal of Molecular Sciences. 2021; 22(22):12455.

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Zughaibi, Torki A., Mohd Suhail, Mohammad Tarique, and Shams Tabrez. 2021. "Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach" International Journal of Molecular Sciences 22, no. 22: 12455.

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