Abstract
Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 385(9972), 977–1010 (2015). • Highlights the lung cancer pathogenesis and global significance.
- 2. . MIR-27a regulates the TGF-β signaling pathway by targeting SMAD2 and SMAD4 in lung cancer. Mol. Carcinog. 56(8), 1992–1998 (2017).
- 3. . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
- 4. . Molecular origins of cancer: lung cancer. N. Engl. J. Med. 359(13), 1367–1380 (2008).
- 5. . The World Cancer Research Fund/American Institute for Cancer Research third expert report on diet, nutrition, physical activity, and cancer: impact and future directions. J. Nutr. 150(4), 663–671 (2020).
- 6. . Quercetin-loaded nanomedicine as oncotherapy. In: Nanomedicine for Bioactives Rahman MBeg SKumar VAhmad F (Eds). Springer, Singapore (2020).
- 7. Flavonoids – chemistry, metabolism, cardioprotective effects, and dietary sources. J. Nutr. Biochem. 7(2), 66–76 (1996).
- 8. . The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic. Res. 22(4), 375–383 (1995).
- 9. Dietary intervention by phytochemicals and their role in modulating coding and non-coding genes in cancer. Int. J. Mol. Sci. 18(6), 1178 (2017).
- 10. . Potential of flavonoids: recent trends and future perspectives. 3 Biotech 3(6), 439–459 (2013).
- 11. . Progress in research on the role of flavonoids in lung cancer. Int. J. Mol. Sci. 20(17), 4291 (2019). •• Overview on the classification, mechanism and therapeutic effects of various flavonoids in lung cancer therapy.
- 12. Multi-task joint learning model for segmenting and classifying tongue images using a deep neural network. IEEE J. Biomed. Health. Inf. 24(9), 2481–2489 (2020).
- 13. Prediction of oral hepatotoxic dose of natural products derived from traditional Chinese medicines based on SVM classifier and PBPK modeling. Arch. Toxicol. 95(5), 1683–1701 (2021).
- 14. . Plant polyphenols and their anti-cariogenic properties: a review. Molecules 16(2), 1486–1507 (2011).
- 15. . Selective targeting of cancer signaling pathways with nanomedicines: challenges and progress. Future Oncol. 16(35), 2959–2979 (2020).
- 16. . Anti-proliferative, apoptotic and signal transduction effects of hesperidin in non-small-cell lung cancer cells. Cell. Oncol. (Dordr.) 38(3), 195–204 (2015).
- 17. . Hesperidin induces apoptosis and G0/G1 arrest in human non-small-cell lung cancer A549 cells. Int. J. Mol. Med. 41(1), 464–472 (2018).
- 18. Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells. Mol. Nutr. Food Res. 55(2), 300–309 (2011).
- 19. Discovery of eriodictyol as putative exportin-1 inhibitor for non-small-cell lung cancer therapy. Preprints (2020).
doi:10.20944/preprints202010.0477.v1 . - 20. The anti-tumor effect of taxifolin on lung cancer via suppressing stemness and epithelial-mesenchymal transition in vitro and oncogenesis in nude mice. Ann. Transl. Med. 8(9), 590 (2020).
- 21. . Immunomodulatory effect of eriocitrin in experimental animals with benzo(a)pyrene-induced lung carcinogenesis. J. Environ. Pathol. Toxicol. Oncol. 39(2), 137–147 (2020).
- 22. Didymin, a dietary flavonoid glycoside from citrus fruits, induces Fas-mediated apoptotic pathway in human non-small-cell lung cancer cells in vitro and in vivo. Lung Cancer 68(3), 366–374 (2010).
- 23. . Flavonoids: Classification, Biosynthesis and Chemical Ecology. In: Justino GC (Ed.). Flavonoids – From Biosynthesis to Human Health. IntechOpen, London (2017).
doi:10.5772/67861Chapter 1 . - 24. . Impact of quercetin, diallyl disulfide and nimbolide on the regulation of nuclear factor kappa B expression in prostate and breast cancer cell lines. Biochem. Pharmacol 2(4), 50 (2013).
- 25. . Antiproliferative and antimetastatic action of quercetin on A549 non-small-cell lung cancer cells through its effect on the cytoskeleton. Acta Histochem. 119(2), 99–112 (2017).
- 26. . Quercetin down-regulates IL-6/STAT-3 signals to induce mitochondrial-mediated apoptosis in a non-small-cell lung-cancer cell line, A549. J. Pharmacopuncture 18(1), 19–26 (2015).
- 27. . Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes. Food Chem. Toxicol. 45(10), 2005–2013 (2007).
- 28. . Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells. Biomed. Pharmacother. 108, 809–816 (2018).
- 29. Myricetin: versatile plant based flavonoid for cancer treatment by inducing cell cycle arrest and ROS-reliant mitochondria-facilitated apoptosis in A549 lung cancer cells and in silico prediction. Mol. Cell. Biochem. 476(1), 57–68 (2021).
- 30. . Isorhamnetin enhances the radiosensitivity of A549 cells through interleukin-13 and the NF-kappaB signaling pathway. Front. Pharmacol. 11, 610772 (2020).
- 31. Isorhamnetin flavonoid synergistically enhances the anticancer activity and apoptosis induction by cis-platin and carboplatin in non-small-cell lung carcinoma (NSCLC). Int. J. Clin. Exp. Pathol. 8(1), 25–37 (2015).
- 32. . Chemistry and biological activities of flavonoids: an overview. Sci. World J. 2013, 162750 (2013).
- 33. . The phosphorylation of IRS1S307 and AktS473 molecules in insulin-resistant C2C12 cells induced with palmitate is influenced by epigallocatechin gallate from green tea. Lipids 54(2-3), 141–148 (2019).
- 34. . Anti-cancer activity of catechin against A549 lung carcinoma cells by induction of cyclin kinase inhibitor p21 and suppression of cyclin E1 and P-AKT. Appl. Sci. 10(6), 2065 (2020).
- 35. The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small-cell lung cancer cells. Clin. Cancer Res. 15(15), 4885–4894 (2009).
- 36. . Gender-dependent expression of alpha and beta estrogen receptors in human nontumor and tumor lung tissue. Mol. Cell. Endocrinol. 188(1-2), 125–140 (2002).
- 37. . Non-small-cell lung cancer and breast carcinoma: chemotherapy and beyond. Lancet Oncol. 7(5), 416–424 (2006).
- 38. . Genistein-induced G2-M arrest, p21WAF1 upregulation, and apoptosis in a non-small-cell lung cancer cell line. Nutr. Cancer 31(3), 184–191 (1998).
- 39. . p53-independent apoptosis induced by genistein in lung cancer cells. Nutr. Cancer 33(2), 125–131 (1999).
- 40. . Genistein enhances the effect of cisplatin on the inhibition of non-small-cell lung cancer A549 cell growth in vitro and in vivo. Oncol. Lett. 8(6), 2806–2810 (2014).
- 41. Genistein exhibits effects via down-regulating FoxM1 in H446 small-cell lung cancer cells. Tumour Biol. 35(5), 4137–4145 (2014).
- 42. . Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small-cell lung cancer cells. Biochem. Pharmacol. 48(6), 1129–1136 (1994).
- 43. Genistein inhibits A549 human lung cancer cell proliferation via miR-27a and MET signaling. Oncol. Lett. 12(3), 2189–2193 (2016).
- 44. Soy isoflavone genistein inhibits hsa_circ_0031250/miR-873-5p/FOXM1 axis to suppress non-small-cell lung cancer progression. IUBMB Life 73(1), 92–107 (2021).
- 45. Genistein promotes ionizing radiation-induced cell death by reducing cytoplasmic Bcl-xL levels in non-small-cell lung cancer. Sci. Rep. 8(1), 328 (2018).
- 46. . Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo. Mol. Biol. Rep. 39(4), 4971–4979 (2012).
- 47. . Daidzein-rich isoflavones aglycone inhibits lung cancer growth through inhibition of NF-kappaB signaling pathway. Immunol. Lett. 222, 67–72 (2020).
- 48. . Anthocyanin supplement as a dietary strategy in cancer prevention and management: a comprehensive review. Crit. Rev. Food Sci. Nutr. 62(26), 7242–7254 (2021).
- 49. Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways. PLOS ONE 8(10), e77270 (2013).
- 50. . Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. Cancer Lett. 235(2), 248–259 (2006).
- 51. . Recent developments in biological activities of chalcones: a mini review. Eur. J. Med. Chem. 85, 758–777 (2014).
- 52. Novel synthetic chalcones induce apoptosis in the A549 non-small-cell lung cancer cells harboring a KRAS mutation. Bioorg. Med. Chem. Lett. 26(23), 5703–5706 (2016).
- 53. A natural chalcone induces apoptosis in lung cancer cells: 3D-QSAR, docking and an in vivo/vitro assay. Sci. Rep. 7(1), 10729 (2017). •• Outlines the therapeutic approaches for various dietary flavonoid-loaded nanoengineered systems in lung cancer therapy.
- 54. . Flavonoid nanoparticles: a promising approach for cancer therapy. Biomolecules 10(9), 1268 (2020).
- 55. Diverse applications of nanomedicine. ACS Nano 11(3), 2313–2381 (2017).
- 56. . Engineering nanoparticles toward the modulation of emerging cancer immunotherapy. Adv. Healthc. Mater. 10(5), 2000845 (2021).
- 57. Nanotechnology: breaking the current treatment limits of lung cancer. Adv. Healthc. Mater. 10(12), 2100078 (2021).
- 58. . The potential of nanomaterials for drug delivery, cell tracking, and regenerative medicine 2014. J. Nanomater. 2015, 1–2 (2015).
- 59. . Application of nanoparticles in the treatment of lung cancer with emphasis on receptors. Front. Pharmacol. 12, 781425 (2021).
- 60. . Molecular insights into potential contributions of natural polyphenols to lung cancer treatment. Cancers (Basel) 11(10), 1565 (2019).
- 61. . The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41, 189–207 (2001).
- 62. . Selective targeting of antibody-conjugated nanoparticles to leukemic cells and primary T-lymphocytes. Biomaterials 26(29), 5898–5906 (2005).
- 63. . Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Rel. 65(1-2), 271–284 (2000).
- 64. . Chiral protein supraparticles for tumor suppression and synergistic immunotherapy: an enabling strategy for bioactive supramolecular chirality construction. Nano Lett. 20(8), 5844–5852 (2020).
- 65. . Turning chiral peptides into a racemic supraparticle to induce the self-degradation of MDM2. J. Adv. Res. S2090-1232(22), 00121–7 (2022). • Focus on flavanol-loaded nanotherapeutics in lung cancer therapy.
- 66. . Nanotechnology based therapeutics for lung disease. Thorax 74(10), 965 (2019).
- 67. . Preparation, in vitro and in vivo evaluation of polymeric nanoparticles based on hyaluronic acid-poly(butyl cyanoacrylate) and D-alpha-tocopheryl polyethylene glycol 1000 succinate for tumor-targeted delivery of morin hydrate. Int. J. Nanomed. 10, 305–320 (2015).
- 68. Designing of fatty acid-surfactant conjugate based nanomicelles of morin hydrate for simultaneously enhancing anticancer activity and oral bioavailability. Colloids Surf. B Biointerfaces 175, 202–211 (2019).
- 69. Amorphous nano morin outperforms native molecule in anticancer activity and oral bioavailability. Drug Dev. Ind. Pharm. 46(7), 1123–1132 (2020).
- 70. . Nano-chemotherapeutic efficacy of (-) -epigallocatechin 3-gallate mediating apoptosis in A549 cells: involvement of reactive oxygen species mediated Nrf2/Keap1signaling. Biochem. Biophys. Res. Commun. 503(3), 1723–1731 (2018).
- 71. A chitosan–PLGA based catechin hydrate nanoparticles used in targeting of lungs and cancer treatment. Saudi J. Biol. Sci. 27(9), 2344–2357 (2020).
- 72. Enhanced chemotherapeutic efficacy of PLGA-encapsulated epigallocatechin gallate (EGCG) against human lung cancer. Int. J. Nanomed. 15, 4417–4429 (2020).
- 73. . Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway. Sci. Rep. 10(1), 5163 (2020).
- 74. The synergistic anticancer effect of dual drug- (cisplatin/epigallocatechin gallate) loaded gelatin nanoparticles for lung cancer treatment. J. Nanomater. 2020, 9181549 (2020).
- 75. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res. 12(10), 3193–3199 (2006).
- 76. . Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer. Int. J. Nanomed. 7, 651–661 (2012).
- 77. . PEG-OCL micelles for quercetin solubilization and inhibition of cancer cell growth. Eur. J. Pharm. Biopharm. 79(2), 268–275 (2011).
- 78. . Ionically crosslinked complex gels loaded with oleic acid-containing vesicles for transdermal drug delivery. Pharmaceutics 12(8), 725 (2020).
- 79. Paclitaxel and quercetin nanoparticles co-loaded in microspheres to prolong retention time for pulmonary drug delivery. Int. J. Nanomed. 12, 8239–8255 (2017).
- 80. . Enhancing tumor cell response to multidrug resistance with pH-sensitive quercetin and doxorubicin conjugated multifunctional nanoparticles. Colloids Surf. B Biointerfaces 156, 175–185 (2017).
- 81. . In vitro evaluation of the inhalable quercetin loaded nanoemulsion for pulmonary delivery. Drug Deliv. Transl. Res. 9(2), 497–507 (2019).
- 82. . Optimization of quercetin loaded palm oil ester based nanoemulsion formulation for pulmonary delivery. J. Oleo Sci. 67(8), 933–940 (2018).
- 83. . RGD-modified nanoliposomes containing quercetin for lung cancer targeted treatment. Onco. Targets Ther. 11, 5397–5405 (2018).
- 84. . In vitro and in vivo anticancer efficacy potential of quercetin loaded polymeric nanoparticles. Biomed. Pharmacother. 106, 1513–1526 (2018).
- 85. Pulmonary delivery of transferrin receptors targeting peptide surface-functionalized liposomes augments the chemotherapeutic effect of quercetin in lung cancer therapy. Int. J. Nanomed. 14, 2879–2902 (2019).
- 86. A self-indicating cellulose-based gel with tunable performance for bioactive agent delivery. J. Drug Deliv. Sci. Technol. 63, 102428 (2021).
- 87. . Dual therapeutic targeting of lung infection and carcinoma using lactoferrin-based green nanomedicine. ACS Biomater. Sci. Eng. 6(10), 5685–5699 (2020).
- 88. Heparin coated meta-organic framework co-delivering doxorubicin and quercetin for effective chemotherapy of lung carcinoma. J. Int. Med. Res. 48(2), 300060519897185 (2020).
- 89. . Co-delivery anticancer drug nanoparticles for synergistic therapy against lung cancer cells. Drug Des. Devel. Ther. 14, 4503–4510 (2020).
- 90. Targeted delivery of quercetin by nanoparticles based on chitosan sensitizing paclitaxel-resistant lung cancer cells to paclitaxel. Mater. Sci. Eng. C Mater. Biol. Appl. 119, 111442 (2021).
- 91. . Myricetin loaded solid lipid nanoparticles upregulate MLKL and RIPK3 in human lung adenocarcinoma. Int. J. Pept. Res. Ther. 26(2), 899–910 (2019).
- 92. . Promoted antitumor activity of myricetin against lung carcinoma via nanoencapsulated phospholipid complex in respirable microparticles. Pharm. Res. 37(4), 82 (2020).
- 93. Folic acid (FA)-conjugated mesoporous silica nanoparticles combined with MRP-1 siRNA improves the suppressive effects of myricetin on non-small-cell lung cancer (NSCLC). Biomed. Pharmacother. 125, 109561 (2020).
- 94. . Bio-inspired synthesis of chitosan/copper oxide nanocomposite using rutin and their activity in human lung cancer cells. Int. J. Biol. Macromol. 141, 476–483 (2019).
- 95. Rutin loaded liquid crystalline nanoparticles inhibit non-small-cell lung cancer proliferation and migration in vitro. Life Sci. 276, 119436 (2021). • Focus on flavone-loaded nanotherapeutics in lung cancer therapy.
- 96. . Apigenin stabilized gold nanoparticles increased radiation therapy efficiency in lung cancer cells. Int. J. Clin. Exp. Med. 10, 13298–13305 (2017).
- 97. . Synergistic apoptotic effects of apigenin TPGS liposomes and tyroservatide: implications for effective treatment of lung cancer. Int. J. Nanomed. 12, 5109–5118 (2017).
- 98. . Targeted hyaluronic acid-based lipid nanoparticle for apigenin delivery to induce Nrf2-dependent apoptosis in lung cancer cells. J. Drug Deliv. Sci. Technol. 49, 268–276 (2019).
- 99. Apigenin-loaded PLGA-DMSA nanoparticles: a novel strategy to treat melanoma lung metastasis. Mol. Pharm. 18(5), 1920–1938 (2021).
- 100. Luteolin nanoparticle in chemoprevention: in vitro and in vivo anticancer activity. Cancer Prev. Res. (Phila.) 7(1), 65–73 (2014).
- 101. Vitamin E TPGS modified liposomes enhance cellular uptake and targeted delivery of luteolin: an in vivo/in vitro evaluation. Int. J. Pharm. 512(1), 262–272 (2016). • Focus on flavanone-loaded nanotherapeutics in lung cancer therapy.
- 102. Hesperetin liposomes for cancer therapy. Curr. Drug Deliv. 13(5), 711–719 (2016).
- 103. . Antioxidant studies of chitosan nanoparticles containing naringenin and their cytotoxicity effects in lung cancer cells. Int. J. Biol. Macromol. 78, 87–95 (2015).
- 104. Biotinylated naringenin intensified anticancer effect of gefitinib in urethane-induced lung cancer in rats: favourable modulation of apoptotic regulators and serum metabolomics. Artif. Cells Nanomed. Biotechnol. 46(Suppl. 3), S598–S610 (2018).
- 105. . Hyaluronic acid decorated naringenin nanoparticles: appraisal of chemopreventive and curative potential for lung cancer. Pharmaceutics 10(1), 33 (2018).
- 106. Formulation design, statistical optimization, and in vitro evaluation of a naringenin nanoemulsion to enhance apoptotic activity in A549 lung cancer cells. Pharmaceuticals (Basel) 13(7), 152 (2020).
- 107. Naringenin-functionalized multi-walled carbon nanotubes: a potential approach for site-specific remote-controlled anticancer delivery for the treatment of lung cancer cells. Int. J. Mol. Sci. 21(12), 4557 (2020).
- 108. . A novel drug delivery system: the encapsulation of naringenin in metal–organic frameworks into liposomes. AAPS PharmSciTech 22(2), 61 (2021). • Focus on isoflavone-loaded nanotherapeutics in lung cancer therapy.
- 109. . Effects of transport inhibitors on the cellular uptake of carboxylated polystyrene nanoparticles in different cell lines. PLOS ONE 6(9), e24438 (2011).
- 110. . Multicompartmental lipid–protein nanohybrids for combined tretinoin/herbal lung cancer therapy. Nanomedicine (Lond.) 14(18), 2461–2479 (2019).
- 111. Inhalable dual-targeted hybrid lipid nanocore-protein shell composites for combined delivery of genistein and all-trans retinoic acid to lung cancer cells. ACS Biomater. Sci. Eng. 6(1), 71–87 (2020).
- 112. . Codelivery of genistein and miRNA-29b to A549 cells using aptamer-hybrid nanoparticle bioconjugates. Nanomaterials (Basel) 9(7), 1052 (2019).
- 113. Multimodal deep learning with feature level fusion for identification of choroidal neovascularization activity in age-related macular degeneration. Acta Ophthalmol. 100(2), e512–e520 (2022).
- 114. . Therapeutic effect of luteolin natural extract versus its nanoparticles on tongue squamous cell carcinoma cell line. (NCT03288298) (2017).