Quercetin Derivatives in Nicotine-Induced Non-Small Cell Lung-Cancer Therapy: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Naser Alsharairi.

Flavonoids are the largest group of polyphenols, represented by many compounds that exhibit high anticancer properties. Quercetin (Q) and its main derivatives (rutin, quercitrin, isoquercitrin, isorhamnetin, tamarixetin, rhamnetin, and hyperoside) in the class of flavonols have been documented to exert anticancer activity. Q has been shown to be useful in the treatment of non-small cell lung cancer (NSCLC), as demonstrated by in vitro/in vivo studies, due to its antitumor, anti-inflammatory, anti-proliferative, anti-angiogenesis, and apoptotic properties. Some flavonoids (flavone, anthocyanins, and proanthocyanidins) have been demonstrated to be effective in nicotine-induced NSCLC treatment. 

  • non-small cell lung cancer
  • quercetin derivatives
  • nicotine
  • rutin
  • isorhamnetin
  • hyperoside
  • rhamnetin
  • rhamnazin
  • quercitrin
  • tamarixetin

1. Introduction

Cigarette smoke contains a large number of carcinogenic compounds, including nitrosamines (nitrosonornicotine, NNN; and 4-methylnitrosamino-1-3-pyridyl-1-butanone, NNK), which are implicated in increasing the risk of NSCLC [4][1]. Nicotine is not regarded as a carcinogenic compound in tobacco and cigarette smoke, but it has the potential to facilitate tumorigenesis [5,6][2][3]. Nicotine and NNK increase the NSCLC risk by upregulating a network of signaling pathways facilitating proliferation, metastasis, and angiogenesis, and inhibiting apoptosis through activation of the nicotinic acetylcholine receptor (α7nAChRs) and beta-adrenergic receptor (β-AdrR) [6,7,8][3][4][5]. Quercetin (Q) and its glycoside isoquercitrin (IQ) and rutin (RU) are natural flavonols found mostly in fruits, and are considered as positive allosteric modulators (PAMs)/selective agonists of human α7nAChR, which makes them potential therapeutic agents in nicotine-induced NSCLC [16,17][6][7]. 

2. Rutin

RU (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside), also known as Q-3-O-rutinoside, is a flavonol compound found in various fruits and vegetables. It is less bioavailable and soluble than Q in humans [31][8]. RU is also absorbed more slowly than Q in the small intestine of rats [32][9]. RU could be useful in the treatment of NSCLC mediated by α7nAChR. RU and Q act on α7nAChR-dependent ion currents. Q induces the enhancement of ACh-induced inward peak currents (IACh) on cells expressing human α7nAChR and increases the extracellular Ca2+ level-mediated potentiation of IAch via interactions with Ca2+-binding sites for α7nAChR in Xenopus oocytes (a system for the expression of plasma membrane transport proteins) [33][10]. Q exhibits differential regulation of α7nAChR channel activity with respect to RU in such a way that Q increases IACh, while RU decreases IACh in Xenopus oocytes expressing human α7AChR, and such effects exist in a voltage-insensitive and non-competitive manner. Q-mediated IACh suppression can be improved when Q is co-administered with RU, suggesting that RU may have a significant role in the regulation of α7nAChR [34][11]. RU was found to inhibit β-amyloid (Aβ) peptide-induced neuronal cytotoxicity, nitric oxide (NO), and the production of reactive oxygen species (ROS) and proinflammatory cytokines by reducing interleukin (IL)-1β and tumor necrosis factor (TNFα) production in microglia [35][12]. Plasma levels of Aβ were found to be significantly increased in patients with multiple cancers, including LC [36][13]. An in vitro study has shown that α-L-rhamnosidase (α-R) cleaves terminal α-rhamnose in flavonoid rutinosides/glycosides (hesperidin, naringin, diosmin, and troxerutin), which increases the anti-proliferative and anti-oxidant activities of RU against various cancer cell lines, including NSCLC (H460) cells [37][14]. In contrast, β-glucosidase (β-G) has been shown to exert high potency against LC tumor growth. β-G converts rutin to rutinose disaccharide and Q through its ability to remove sugar moieties such as glucose linked to flavonoids in positions 3 and 7 of the C ring [38][15]. β-G has been described as the key glycoprotein-processing enzyme that inhibits the expression of p53 in NSCLC cells [39][16]. Knockout of β-G was found to inhibit cell migration/metastasis and induce apoptosis and/or autophagy in NSCLC cells through the suppression of RTK signaling pathways [40][17]. α-R may convert RU into IQ with high bioactivity and bioavailability by combining with β-G [41][18]. Thus, α-R coupled with β-G provides high bioactive effects, which inhibit the proliferation and induction of apoptosis in NSCLC cells. Recent molecular docking studies showed that the OH groups of RU (C7-OH) form stable H-bond interactions with several amino acid residues, including serine, aspartic acid, phenylalanine, glutamine, glutamic acid, and arginine [42][19]. Therefore, these OH groups may create interactions with amino acid residues in the binding pocket of α7nAChR, displaying complex modulation of the receptor. A few studies investigating the therapeutic efficacy of RU in nicotine-induced NSCLC showed that the mechanisms underlying its effects have not been explored. Transformation of rutin to quercetin-3-β-D-glucoside (Q3G) using α-R and β-G from a crude enzyme extract of Aspergillus niger (A. niger) has been shown to inhibit NSCLC cell proliferation [43][20]. A study has demonstrated that RU-loaded liquid crystalline nanoparticles exert anti-proliferative/anti-migratory and apoptotic effects on NSCLC cells [44][21]. RU reduces superoxide anion/intracellular ROS production and suppresses the proliferation and migration/adhesion of NSCLC cells, although it showed cytotoxic effects at concentrations higher than 500 µM (IC50 = 559.83 µM) [45][22]. RU from Artemesia judaica L. (A. judaica L.) ethanolic extract showed apoptotic potential against NSCLC cells and arrested the cell cycle at the G2/M phase. A cytotoxic activity of A. judaica L. extract was reported against A549 cells (IC50 = 14.2 μg/mL). This may be due to the presence of several extracts of different polarities [46][23]. RU has shown antioxidant effects on NSCLC cells by decreasing NNK-induced intracellular ROS and inhibiting the DNA damage induced by β-carotene [47][24]. Thus, RU may have therapeutic potential in nicotine-induced NSCLC cells by inhibiting proliferation, migration, and adhesion, and promoting apoptosis. RU also has a beneficial effect as a potential antioxidant in inhibiting NNK-induced DNA damage in NSCLC cells.

3. Isorhamnetin

Isorhamnetin (IS) (3′-methoxy-3,4′,5,7-tetrahydroxyflavone), a flavonol compound found in the leaves of medicinal plants such as Hippophae rhamnoides L. (H. rhamnoides L.) and Ginkgo biloba L. (G. biloba L.) has a wide range of therapeutic effects against several diseases, such as cerebrovascular diseases and atherosclerosis, It has also shown anti-tumor effects against various common cancers, including LC [48][25]. A few in vivo studies so far have shown a high IS bioavailability. Phytic acid improves the oral absorption of flavone compounds of H. rhamnoides L, including IS [49][26]. The bioavailability of IS increased when it was coingested with G. biloba L. extract solid dispersions and phospholipid complexes [50][27]. The therapeutic effects of IS against nicotine-induced NSCLC may be related to the inhibition of α7nAChR and its downstream signaling pathways. However, whether IS has potential α7-PAM activity remains unknown. IS is structurally similar to Q, which has an OH group at C-3. IS has four OH groups at the C-3,5,7,4′ positions, with one OH group on the B and C rings and two OH groups on the A ring [27,28][28][29]. IS also has one methoxy group in the C-5′ position on the B ring [27,28][28][29]. Thus, IS may be an effective anti-NSCLC agent by binding to the molecules involved in the α7nAChR-mediated signaling pathways. Another possible explanation for the anti-tumor activities of IS against nicotine-induced NSCLC might be due to the enzymatic de-glycosylation of IS by α-R and β-G [51][30], which could lead to improved efficacy of IS for the treatment of NSCLC. IS may interact with the active site of both α-R and β-G, resulting in the inhibition of signaling pathway regulation of cellular processes implicated in nicotine-induced NSCLC. IS may have anti-proliferative and apoptotic/autophagic effects against nicotine-induced NSCLC via regulation of α7nAChR and its downstream signaling pathways. IS inhibits proliferation/colony formation ability and promotes the apoptosis/autophagy of NSCLC cells in a time and dose-dependent manner via the mitochondria-dependent apoptosis pathway [52][31]. Treatment with IS demonstrated significant inhibition of migration and invasion via inactivation of the oncogenic kinase signaling pathway [53][32].

4. Hyperoside

Hyperoside (HP), also termed Q 3-O-β-D-galactopyranoside, a naturally occurring flavonol that is widely present in plants such as Polygonum aviculare, Crataegus pinnatifida, and Hypericum monogynum, exerts a wide range of anticancer effects [29,54][33][34]. The therapeutic effect of HP on nicotine-induced NSCLC is still unclear, but it may be attributed to its aglycone Q, which has a great binding affinity for human α7nAChR [29][33]. HP may have high affinity and potential for binding to the active site of α7nAChR. The anti-NSCLC activity of HP may depend on its having eight OH groups on the A, B, and C-rings of their structure, with two OH groups on the B ring (positions 3′ and 4′), two OH groups on the A ring (positions 5 and 7), and four OH groups in the glycosides linked to the C ring (positions 2″, 3″, 4″, and 5″) [27,29][28][33]. In vivo, low HP bioavailability may be due to its poor oral absorption [55,56][35][36]. A few studies suggest that HP treatment exhibits a range of effects against nicotine-induced NSCLC, including anti-proliferative, anti-migration, anti-invasion, anti-inflammatory, and apoptotic/autophagic activities. HP has been reported to suppress proliferation and promote apoptosis of T790M-positive NSCLC cells by increasing forkhead box protein O1 (FoxO1) expression in colon cancer-associated transcript 1 (CCAT1)-knockdown NSCLC cells [57][37]. HP inhibits the expression of genes associated with tumor migration and invasion in NSCLC cells by suppressing signaling pathways involving tumor metastatic genes [58][38]. HP decreases viability and induces apoptosis of NSCLC cells by upregulating pro-apoptotic-related gene expression through activation of apoptotic pathways [59][39]. HP activates apoptosis and autophagy in proliferating NSCLC cells by increasing apoptotic/autophagic-related gene expression via a range of signaling pathways associated with tumorigenesis [60][40]. HP regulates genes involved in apoptosis while downregulating genes involved in proliferation, migration, invasion, and inflammation of NSCLC cells via inhibiting the NF-kB signaling pathway [61][41]. HP inhibits proliferation, increases apoptosis, and causes arrested growth of NSCLC cells at the G1/S phase by decreasing the protein expression of cyclin-dependent kinase (CCND1) and coding sequence (CDK 4 & 6) through its interaction with the microRNA-let7a-5p [62][42]. HP significantly inhibited proliferation, migration, invasion, and angiogenesis; induced apoptosis; and arrested the cell cycle at the S phase in NSCLC cells, mediated through upregulating pro-apoptotic and downregulating anti-apoptotic protein levels [63][43]. HP reduces the inflammation of NSCLC cells by decreasing Mycoplasma pneumoniae pneumonia (MPP)-induced pro-inflammatory cytokines production through NF-κB signaling pathway inactivation [64][44]. HP reduces hypoxia-induced viability and proliferation of NSCLC cells, as demonstrated by upregulating the expression of heme oxygenase-1 (HO-1) through activating AMP-activated protein kinase (AMPK) [65][45].

5. Rhamnetin and Rhamnazin

Rhamnetin (RT) and rhamnazin (RZ) are methylated QDs distributed widely in fruits and vegetables that exert antibacterial, anti-inflammatory, antioxidant, and anticancer properties [27,66][28][46]. Previous evidence has demonstrated that the methoxy groups produce steric hindrance and reduce the free radical scavenging ability of flavonoids. However, the OH groups endow flavonols with high radical scavenging capability [67][47]. RT and RZ are structurally similar to IS but differ from other flavonols by having methoxy groups on the A and B rings [27,28][28][29]. RT (7′-O-methoxy Q) contains a methyl group at the 7′ position on the A ring, while RZ (3′,7′-dimethylquercetin) has two methyl groups at the 3 and 7′ positions on the A and B rings [27,30][28][48]. RT and RZ have an OH group at C-3, which plays a significant role in anti-tumor activity against nicotine-induced NSCLC. RT possesses four OH groups at C-5, 3, 3′, and 4′, with one OH group on the A and C rings and two OH groups on the B ring. RZ has three OH groups in its structure at the 5 position on the A ring, the 3 position on the C ring, and the 4′ position on the B ring [27,30][28][48]. RT has been shown to displace a selective α7nAChR ligand, methyllycaconitine [3H]-MLA, or an αβ2 selective ligand, [3H]-cytisine, with the lowest cytotoxicity activity (IC50) of nicotine, resulting in inhibited NO and TNFα release [68][49]. RT also exerts α7nAChRs agonist activity in vivo, as demonstrated by reduced excitotoxicity following ethanol exposure and neuroinflammation by decreasing lipopolysaccharide (LPS)-induced TNFα and NO production [69][50]. RZ may have a significant role in anti-angiogenic effects in NSCLC cells, as demonstrated by a xenograft mouse model. RZ suppresses in vivo angiogenesis mediated by NSCLC cells by inhibiting vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation through anti-programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) signaling pathway inactivation. Treatment with RZ (20 μM) and anti-CD3 antibody (1 μg/mL) exhibits cytotoxic effects on NSCLC cells, promotes T cell proliferation, and increases the production of cytotoxic mediators [70][51].

6. Quercitrin

Quercitrin (QU), also known as Q-3-O-rhamnoside, is a Q derivative that is structurally similar to HP. QU has seven OH groups on the A, B, and C rings, with two OH groups on the A ring (positions 5 and 7), two OH groups on the B ring (positions 3′ and 4′) and three OH groups in the glycosides linked to the C ring. QU differs from QDs by having one methyl group in the glycosides linked to the C ring, which makes its anti-NSCLC ability lower than the other derivatives [27,30][28][48]. Thus, Qu would be expected to have lower levels of effectiveness as an anti-NSCLC agent than other QDs in binding to the α7nAChR-mediated signaling pathways. A few studies have demonstrated that QU exerts anti-proliferative, anti-migration/invasion, and apoptotic effects on NSCLC cells. QU inhibits proliferation and induces apoptosis in NSCLC cells via increasing caspase-3 enzyme activity and the nucleosomal enrichment factor, and inducing the loss of mitochondrial membrane potential. QU exerts cytotoxic effects on NSCLC cells in a dose-dependent manner (50 μmol), which may be due to inducing lactate dehydrogenase (LDH) release to baseline levels of toxicity [71][52]. NSCLC cell migration and invasion has been shown to be reduced by QU treatment at different concentrations by inhibiting the transcript levels of Gap Junction Protein Beta 2 (GJB2) in these cells [72][53].

7. Tamarixetin

Tamarixetin (TA), also called 4′-O-methoxy Q, is a derivative that has four OH groups on C 3, 5, 7, and 3′ [30][48], among which the OH group at C-3 may improve the anti-tumor activity against NSCLC [67][47]. However, TA has a methyl group at the 4′ position on the B ring [30][48]. Only one study showed that TA and IS inhibit the proliferation of NSCLC cells. This inhibition was accompanied by increased apoptosis-related gene expression. Cytotoxicity analysis has indicated cytotoxic activity of TA and IS with an IC50 value between 15–26 μM in NSCLC cells. This may be due to the combination of different flavonoids, which increases the cytotoxic potencies of these methylquercetins [73][54].

References

  1. Li, Y.; Hecht, S.S. Carcinogenic components of tobacco and tobacco smoke: A 2022 update. Food Chem. Toxicol. 2022, 165, 113179.
  2. Hecht, S.S. Lung Carcinogenesis by tobacco smoke. Int. J. Cancer 2012, 131, 2724–2732.
  3. Warren, G.W.; Singh, A.K. Nicotine and lung cancer. J. Carcinog. 2013, 12, 1.
  4. Xue, J.; Yang, S.; Seng, S. Mechanisms of cancer induction by tobacco-specific NNK and NNN. Cancers 2014, 6, 1138–1156.
  5. Wang, S.; Hu, Y. α7 nicotinic acetylcholine receptors in lung cancer (Review). Oncol. Lett. 2018, 16, 1375–1382.
  6. Nielsen, B.E.; Bermudez, I.; Bouzat, C. Flavonoids as positive allosteric modulators of α7 nicotinic receptors. Neuropharmacology 2019, 160, 107794.
  7. Ximenis, M.; Mulet, J.; Sala, S.; Sala, F.; Criado, M.; González-Muñiz, R.; Jesús Pérez de Vega, M. Natural polyhydroxy flavonoids, curcuminoids, and synthetic curcumin analogs as α7 nAChRs positive allosteric modulators. Int. J. Mol. Sci. 2021, 22, 973.
  8. Thilakarathna, S.H.; Rupasinghe, H.P.V. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013, 5, 3367–3387.
  9. Carbonaro, M.; Grant, G. Absorption of quercetin and rutin in rat small intestine. Ann. Nutr. Metab. 2005, 49, 178–182.
  10. Lee, B.; Choi, S.; Shin, T.; Pyo, M.K.; Hwang, S.; Kim, B.; Lee, S.; Lee, J.; Kim, H.; Park, H.; et al. Quercetin enhances human α7 nicotinic acetylcholine receptor-mediated ion current through interactions with Ca(2+) binding sites. Mol. Cells 2010, 30, 245–253.
  11. Lee, B.; Choi, S.; Kim, H.; Jung, S.; Hwang, S.; Pyo, M.; Rhim, H.; Kim, H.; Kim, H.; Lee, S.; et al. Differential effects of quercetin and quercetin glycosides on human α7 nicotinic acetylcholine receptor-mediated ion currents. Biomol. Ther. 2016, 24, 410–417.
  12. Wang, S.; Wang, Y.; Su, Y.; Zhou, W.; Yang, S.; Zhang, R.; Zhao, M.; Li, Y.; Zhang, Z.; Zhan, D.; et al. Rutin inhibits β-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. Neurotoxicology 2012, 33, 482–490.
  13. Jin, W.; Bu, X.; Liu, Y.; Shen, L.; Zhuang, Z.; Jiao, S.; Zhu, C.; Wang, Q.; Zhou, H.; Zhang, T.; et al. Plasma amyloid-beta levels in patients with different types of cancer. Neurotox. Res. 2017, 31, 283–288.
  14. Branco de Araújo, M.E.M.; Franco, Y.E.M.; Alberto, T.G.; Sobreiro, M.A.; Conrado, M.A.; Priolli, D.G.; Frankland Sawaya, A.C.H.; Ruiz, A.L.T.G.; de Carvalho, J.E.; de Oliveira Carvalho, P. Enzymatic de-glycosylation of rutin improves its antioxidant and antiproliferative activities. Food Chem. 2013, 141, 266–273.
  15. Nam, H.; Hong, S.; Shin, K.; Oh, D. Quercetin production from rutin by a thermostable β-rutinosidase from Pyrococcus furiosus. Biotechnol. Lett. 2012, 34, 483–489.
  16. Suradej, B.; Pata, S.; Kasinrerk, W.; Cressey, R. Glucosidase II exhibits similarity to the p53 tumor suppressor in regards to structure and behavior in response to stress signals: A potential novel cancer biomarker. Oncol. Rep. 2013, 30, 2511–2519.
  17. Khaodee, W.; Udomsom, S.; Kunnaja, P.; Cressey, R. Knockout of glucosidase II beta subunit inhibits growth and metastatic potential of lung cancer cells by inhibiting receptor tyrosine kinase activities. Sci. Rep. 2019, 9, 10394.
  18. Li, B.; Peng, B.; Zhang, T.; Li, Y.; Ding, G. A spectrophotometric method for high-throughput screening of α-l-rhamnosidase activity on rutin coupled with a β-d-glucosidase assay. 3 Biotech 2019, 9, 227.
  19. Tuan, N.N.; Thi, H.N.; Le Thi My, C.; Hai, T.X.; Trung, H.T.; Kim, A.N.T.; Tan, T.N.; Le Van, T.; Nguyen, C.Q.; De Tran, Q.; et al. Inhibition of α-glucosidase, acetylcholinesterase, and nitric oxide production by phytochemicals isolated from Millettia speciosa-In vitro and molecular docking studies. Plants 2022, 11, 388.
  20. You, H.J.; Ahn, H.J.; Ji, G.E. Transformation of rutin to antiproliferative quercetin-3-glucoside by Aspergillus niger. J. Agric. Food Chem. 2010, 58, 10886–10892.
  21. Paudel, K.R.; Wadhwa, R.; Tew, X.N.; Lau, N.J.X.; Madheswaran, T.; Panneerselvam, J.; Zeeshan, F.; Kumar, P.; Gupta, G.; Anand, K.; et al. Rutin loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro. Life Sci. 2021, 276, 119436.
  22. Ben Sghaier, M.; Pagano, A.; Mousslim, M.; Ammari, Y.; Kovacic, H.; Luis, J. Rutin inhibits proliferation, attenuates superoxide production and decreases adhesion and migration of human cancerous cells. Biomed. Pharmacother. 2016, 84, 1972–1978.
  23. Goda, M.S.; Nafie, M.S.; Awad, B.M.; Abdel-Kader, M.S.; Ibrahim, A.K.; Badr, J.M.; Eltamany, E.E. In vitro and in vivo studies of anti-lung cancer activity of Artemesia judaica L. crude extract combined with LC-MS/MS metabolic profiling, docking simulation and HPLC-DAD quantification. Antioxidants 2022, 11, 17.
  24. Yeh, S.-L.; Wang, W.-Y.; Huang, C.-S.; Hu, M.-L. Flavonoids suppresses the enhancing effect of beta-carotene on DNA damage induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A549 cells. Chem. Biol. Interact. 2006, 160, 175–182.
  25. Gong, G.; Guan, Y.-Y.; Zhang, Z.-L.; Rahman, K.; Wang, S.-J.; Zhou, S.; Luan, X.; Zhang, H. Isorhamnetin: A review of pharmacological effects. Biomed. Pharmacother. 2020, 128, 110301.
  26. Xie, Y.; Luo, H.; Duan, J.; Hong, C.; Ma, P.; Li, G.; Zhang, T.; Wu, T.; Ji, G. Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L. Fitoterapia 2014, 93, 216–225.
  27. Chen, Z.-P.; Sun, J.; Chen, H.-X.; Xiao, Y.-Y.; Liu, D.; Chen, J.; Cai, H.; Cai, B.-C. Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats. Fitoterapia 2010, 81, 1045–1052.
  28. Khan, F.; Niaz, K.; Maqbool, F.; Hassan, F.I.; Abdollahi, M.; Venkata, K.C.N.; Nabavi, S.M.; Bishayee, A. Molecular targets underlying the anticancer effects of quercetin: An update. Nutrients 2016, 8, 529.
  29. He, Y.-Q.; Zhou, C.-C.; Yu, L.-Y.; Wang, L.; Deng, J.-L.; Tao, Y.-L.; Zhang, F.; Chen, W.-S. Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms. Pharmacol. Res. 2021, 163, 105224.
  30. Fang, X.; Dong, Y.; Xie, Y.; Wang, L.; Wang, J.; Liu, Y.; Zhao, L.; Cao, F. Effects of β-glucosidase and α-rhamnosidase on the contents of flavonoids, ginkgolides, and aroma components in ginkgo tea drink. Molecules 2019, 24, 2009.
  31. Ruan, Y.; Hu, K.; Chen, H. Autophagy inhibition enhances isorhamnetin-induced mitochondria-dependent apoptosis in non-small cell lung cancer cells. Mol. Med. Rep. 2015, 12, 5796–5806.
  32. Luo, W.; Liu, Q.; Jiang, N.; Li, M.; Shi, L. Isorhamnetin inhibited migration and invasion via suppression of Akt/ERK-mediated epithelial-to-mesenchymal transition (EMT) in A549 human non-small-cell lung cancer cells. Biosci. Rep. 2019, 39, BSR20190159.
  33. Xu, S.; Chen, S.; Xia, W.; Sui, H.; Fu, X. Hyperoside: A review of its structure, synthesis, pharmacology, pharmacokinetics and toxicity. Molecules 2022, 27, 3009.
  34. Wang, Q.; Wei, H.-C.; Zhou, S.-J.; Li, Y.; Zheng, T.-T.; Zhou, C.-Z.; Wan, X.-H. Hyperoside: A review on its sources, biological activities, and molecular mechanisms. Phytother. Res. 2022, 36, 2779–2802.
  35. Li, Z.; Meng, F.; Zhang, Y.; Sun, L.; Yu, L.; Zhang, Z.; Peng, S.; Guo, J. Simultaneous quantification of hyperin, reynoutrin and guaijaverin in mice plasma by LC-MS/MS: Application to a pharmacokinetic study. Biomed. Chromatogr. 2016, 30, 1124–1130.
  36. Yuan, W.; Wang, J.; An, X.; Dai, M.; Jiang, Z.; Zhang, L.; Yu, S.; Huang, X. UPLC-MS/MS method for the determination of hyperoside and application to pharmacokinetics study in rat after different administration routes. Chromatographia 2021, 84, 249–256.
  37. Hu, Z.; Zhao, P.; Xu, H. Hyperoside exhibits anticancer activity in non-small cell lung cancer cells with T790M mutations by upregulating FoxO1 via CCAT1. Oncol. Rep. 2020, 43, 617–624.
  38. Yang, Y.; Sun, Y.; Guo, X.; Zhong, C.; Li, Z. Hyperoside inhibited the migration and invasion of lung cancer cells through the upregulation of PI3K/AKT and p38 MAPK pathways. Int. J. Clin. Exp. Pathol. 2017, 10, 9382–9390.
  39. Yang, Y.; Tantai, J.; Sun, Y.; Zhong, C.; Li, Z. Effect of hyperoside on the apoptosis of A549 human non-small cell lung cancer cells and the underlying mechanism. Mol. Med. Rep. 2017, 16, 6483–6488.
  40. Fu, T.; Wang, L.; Jin, X.-N.; Sui, H.-J.; Liu, Z.; Jin, Y. Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro. Acta Pharmacol. Sin. 2016, 37, 505–518.
  41. Lü, P. Inhibitory effects of hyperoside on lung cancer by inducing apoptosis and suppressing inflammatory response via caspase-3 and NF-κB signaling pathway. Biomed. Pharmacother. 2016, 82, 216–225.
  42. Li, J.-P.; Liao, X.-H.; Xiang, Y.; Yao, A.; Song, R.-H.; Zhang, Z.-J.; Huang, F.; Dai, Z.-T.; Zhang, T.-C. Hyperoside and let-7a-5p synergistically inhibits lung cancer cell proliferation via inducing G1/S phase arrest. Gene 2018, 679, 232–240.
  43. Liu, Y.-H.; Liu, G.-H.; Mei, J.-J.; Wang, J. The preventive effects of hyperoside on lung cancer in vitro by inducing apoptosis and inhibiting proliferation through Caspase-3 and P53 signaling pathway. Biomed. Pharmacother. 2016, 83, 381–391.
  44. Liu, F.; Zhao, Y.; Lu, J.; Chen, S.; Zhang, X.; Mao, W. Hyperoside inhibits proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumonia. Mol. Cell. Biochem. 2019, 453, 179–186.
  45. Chen, D.; Wu, Y.-X.; Qiu, Y.-B.; Wan, B.-B.; Liu, G.; Chen, G.-L.; Lu, M.-D.; Pang, Q.-F. Hyperoside suppresses hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis. Phytomedicine 2020, 67, 153138.
  46. Medeiros, D.L.; Lima, E.T.G.; Silva, J.C.; Medeiros, M.A.; Pinheiro, E.B.F. Rhamnetin: A review of its pharmacology and toxicity. J. Pharm. Pharmacol. 2022, 74, 793–799.
  47. Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002, 13, 572–584.
  48. Magar, R.T.; Sohng, J.K. A review on structure, modifications and structure-activity relation of quercetin and its derivatives. J. Microbiol. Biotechnol. 2020, 30, 11–20.
  49. Lutz, J.A.; Kulshrestha, M.; Rogers, D.T.; Littleton, J.M. A nicotinic receptor-mediated anti-inflammatory effect of the flavonoid rhamnetin in BV2 microglia. Fitoterapia 2014, 98, 11–21.
  50. Lutz, J.A.; Carter, M.; Fields, L.; Barron, S.; Littleton, J.M. The dietary flavonoid rhamnetin inhibits both inflammation and excitotoxicity during ethanol withdrawal in rat organotypic hippocampal slice cultures. Alcohol. Clin. Exp. Res. 2015, 39, 2345–2353.
  51. Wang, S.S.; Liu, Y.; Zhang, X.T.; Yu, D.Q. Rhamnazin enhanced anti-tumor efficacy of anti-PD-1 therapy for lung cancer in mice through inhibition of PD-L1 expression. Tohoku J. Exp. Med. 2023, 260, 63–73.
  52. Cincin, Z.P.; Unlu, M.; Kiran, B.; Bireller, E.S.; Baran, Y.; Cakmakoglu, B. Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch. Med. Res. 2014, 45, 445–454.
  53. Li, D.Y.; Yue, L.X.; Wang, S.G.; Wang, T.X. Quercitrin restrains the growth and invasion of lung adenocarcinoma cells by regulating gap junction protein beta 2. Bioengineered 2022, 13, 6126–6135.
  54. Sak, K.; Lust, H.; Kase, M.; Jaal, J. Cytotoxic action of methylquercetins in human lung adenocarcinoma cells. Oncol. Lett. 2018, 15, 1973–1978.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback