Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma

Abstract

Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.

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References

  1. 1.

    Abolmaali SS, Tamaddon AM, Salmanpour M, Mohammadi S, Dinarvand R. Block ionomer micellar nanoparticles from double hydrophilic copolymers, classifications and promises for delivery of cancer chemotherapeutics. Eur J Pharm Sci. 2017;104:393–405.

    CAS  PubMed  Google Scholar 

  2. 2.

    Aggarwal, Surh YJ. In: Shishodia S, editor. In the molecular targets and therapeutic uses of curcumin in health and disease (series volume 595 ed.). New York: Springer; 2007. p. 1–75.

    Google Scholar 

  3. 3.

    Akhtar N. Vesicles: a recently developed novel carrier for enhanced topical drug delivery. Curr Drug Deliv. 2014;11(1):87–97.

    CAS  PubMed  Google Scholar 

  4. 4.

    Alam S, Panda JJ, Chauhan VS. Novel dipeptide nanoparticles for effective curcumin delivery. Int J Nanomedicine. 2012;7:4207–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Alexander A, Dwivedi S, Ajazuddin GTK, Saraf S, Saraf S, Tripathi DK. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release. 2012;164(1):26–40. https://doi.org/10.1016/j.jconrel.2012.09.017.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    American Academy of Dermatology Association. 2018. Skin cancer. Retrieved 03/10, 2018, from https://www.aad.org/media/stats/conditions/skin-cancer.

  7. 7.

    American Cancer Society. 2018. Key statistics for melanoma skin cancer. Retrieved 03/10, 2018, from https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html.

  8. 8.

    Anand P, Kunnumakkara A, Newman R, Aggarwal B. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18.

    CAS  PubMed  Google Scholar 

  9. 9.

    Androutsopoulos VP, Fragiadaki I, Tosca A. Activation of ERK1/2 is required for the antimitotic activity of the resveratrol analogue 3,4,5,4′-tetramethoxystilbene (DMU-212) in human melanoma cells. Exp Dermatol. 2015;24(8):632–4.

    CAS  PubMed  Google Scholar 

  10. 10.

    Androutsopoulos VP, Fragiadaki I, Spandidos DA, Tosca A. The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action. Int J Oncol. 2016;49(4):1305–14.

    CAS  PubMed  Google Scholar 

  11. 11.

    Ansari K, Vavia P, Trotta F, Cavalli R. Cyclodextrin-based nanosponges for delivery of resveratrol: in vitro characterisation, stability, cytotoxicity and permeation study. AAPS PharmSciTech. 2011;12(1):279–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Anselmo AC, Mitragotri S. An overview of clinical and commercial impact of drug delivery systems. J Control Release. 2014;190:15–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Asensi M, Ortega A, Mena S, Feddi F, Estrela J. Natural polyphenols in cancer therapy. Crit Rev Clin Lab Sci. 2011;48(5–6):197–216. https://doi.org/10.3109/10408363.2011.631268.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL. Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. 2009. https://doi.org/10.1016/j.abb.2009.01.018.

  16. 16.

    Barry B. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14(2):101–14. https://doi.org/10.1016/s0928-0987(01)00167-1.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Barui S, Saha S, Yakati V, Chaudhuri A. Systemic codelivery of a homoserine derived ceramide analogue and curcumin to tumor vasculature inhibits mouse tumor growth. Mol Pharm. 2015;13(2):404–19.

    Google Scholar 

  18. 18.

    Barui S, Saha S, Yakati V, Chaudhuri A. Systemic Codelivery of a Homoserine Derived Ceramide Analogue and Curcumin to Tumor Vasculature Inhibits Mouse Tumor Growth. Mol Pharm. 2016;13(2):404–19.

  19. 19.

    Bellocq N, Pun S, Jensen G, Davis M. Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjug Chem. 2003;14(6):1122–32.

    CAS  PubMed  Google Scholar 

  20. 20.

    Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica. 2013;2013.

  21. 21.

    Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, et al. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007;109(6):2293.

    CAS  PubMed  Google Scholar 

  22. 22.

    Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology (Williston Park, NY). 2009;23(6):488–96.

    Google Scholar 

  23. 23.

    Bhattacharya S, Darjatmoko S, Polans A. Resveratrol modulates the malignant properties of cutaneous melanoma via changes in the activation and attenuation of the anti-apoptotic proto-oncogenic protein Akt/PKB. Melanoma Res. 2011;21(3):180–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bhattacharyya SS, Paul S, De A, Das D, Samadder A, Boujedaini N, et al. Poly (lactide-co-glycolide) acid nanoencapsulation of a synthetic coumarin: cytotoxicity and bio-distribution in mice, in cancer cell line and interaction with calf thymus DNA as target. Toxicol Appl Pharmacol. 2011;253(3):270–81. https://doi.org/10.1016/j.taap.2011.04.010.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bishayee K, Khuda-Bukhsh A, Huh S. PLGA-loaded gold-nanoparticles precipitated with quercetin downregulate HDAC-akt activities controlling proliferation and activate p53-ROS crosstalk to induce apoptosis in hepatocarcinoma cells. Mol Cell. 2015;38(6):518.

    CAS  Google Scholar 

  26. 26.

    Boesch-Saadatmandi C, Loboda A, Wagner AE, Stachurska A, Jozkowicz A, Dulak J, et al. Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155. J Nutr Biochem. 2011;22(3):293–9.

    CAS  PubMed  Google Scholar 

  27. 27.

    Boesch-Saadatmandi C, Wagner AE, Wolffram S, Rimbach G. Effect of quercetin on inflammatory gene expression in mice liver in vivo—role of redox factor 1, miRNA-122 and miRNA-125b. Pharmacol Res. 2012;65(5):523–30.

    CAS  PubMed  Google Scholar 

  28. 28.

    Bommarito AA. In JoAl’s Products LLC (Ed.), Topical turmeric skin care products (US7763289B2 ed.). US; 2005.

  29. 29.

    Bouska A, Lushnikova T, Plaza S, Eischen CM. Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol. 2008;28(15):4862–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Bray S, Schorl C, Hall P. The challenge of p53: linking biochemistry, biology, and patient management. Stem Cells. 1998;16(4):248–60.

    CAS  PubMed  Google Scholar 

  31. 31.

    Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv. 2006;13(3):175–87.

    CAS  PubMed  Google Scholar 

  32. 32.

    Bunney TD, Katan M. Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer. 2010;10(5):342.

    CAS  PubMed  Google Scholar 

  33. 33.

    Bush JA, Cheung KJ, Li G. Curcumin induces apoptosis in human melanoma cells through a fas receptor/caspase-8 pathway independent of p53. US Natl Library Med. 2001;271(2):305–14.

    CAS  Google Scholar 

  34. 34.

    Caddeo C, Nacher A, Vassallo A, Armentano MF, Pons R, Fernàndez-Busquets X, et al. Effect of quercetin and resveratrol co-incorporated in liposomes against inflammatory/oxidative response associated with skin cancer. Int J Pharm. 2016;513(1–2):153–63.

    CAS  PubMed  Google Scholar 

  35. 35.

    Cao H. A mechanistic study on the anti-melanoma action of quercetin (Doctoral dissertation, Hong Kong Baptist University.). 2015.

  36. 36.

    Cao H, Cheng C, Su T, Fu X, Guo H, Li T, et al. Quercetin inhibits HGF/c-met signaling and HGF-stimulated melanoma cell migration and invasion. Mol Cancer. 2015;14:103.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Carletto B, Berton J, Ferreira TN, Dalmolin LF, Paludo KS, Mainardes RM, et al. Resveratrol-loaded nanocapsules inhibit murine melanoma tumor growth. Colloids Surf B: Biointerfaces. 2016;144:65–72.

    CAS  PubMed  Google Scholar 

  38. 38.

    Cevc G, Gebauer D, Stieber J, Schätzlein A, Blume G. Ultraflexible vesicles, transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin. Biochim Biophys Acta. 1998;1368(2):201–15.

    CAS  PubMed  Google Scholar 

  39. 39.

    Chang A, Karnell L, Menck H. The national cancer data base report on cutaneous and noncutaneous melanoma. 1998;83(8):1664–78.

  40. 40.

    Chen J, Li L, Su J, Li B, Chen T, Wong Y. Synergistic apoptosis-inducing effects on A375 human melanoma cells of natural borneol and curcumin. PLoS One. 2014;9(6):e101277.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Chen Y, Wu Q, Zhang Z, Yuan L, Liu X, Zhou L. Preparation of curcumin-loaded liposomes and evaluation of their skin permeation and pharmacodynamics. Molecules (Basel, Switzerland). 2012;17(5):5972–87.

    CAS  Google Scholar 

  42. 42.

    Coleman W. In: Coleman W, Tsongalis GJ, editors. Diagnostic molecular pathology. London: Elsevier Academic Press; 2016.

    Google Scholar 

  43. 43.

    Cosco D, Paolino D, Maiuolo J, Marzio LD, Carafa M, Ventura CA, et al. Ultradeformable liposomes as multidrug carrier of resveratrol and 5-fluorouracil for their topical delivery. Int J Pharm. 2015;489(1–2):1–10.

    CAS  PubMed  Google Scholar 

  44. 44.

    Dandamudi S, Campbell RB. Development and characterization of magnetic cationic liposomes for targeting tumor microvasculature. Biochim Biophys Acta Biomembr. 2007;1768(3):427–38.

    CAS  Google Scholar 

  45. 45.

    Davies MA. The role of the PI3K–AKT pathway in melanoma. Cancer J. 2012;18(2):142–7.

    CAS  PubMed  Google Scholar 

  46. 46.

    De Unamuno B, Palanca S, Botella R. Update on melanoma epigenetics. Curr Opin Oncol. 2015;27(5):420–6.

    PubMed  Google Scholar 

  47. 47.

    Deepthi CHN, Kumar V, Babu R, Darshini U. Role of tumor suppressor protein p53 in apoptosis and cancer therapy. J Cancer Sci Ther. 2011;03(06).

  48. 48.

    Desai P, Patlolla RR, Singh M. Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery. Mol Membr Biol. 2010;27(7):247–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Deshmukh AS, Chauhan PN, Noolvi MN, Chaturvedi K, Ganguly K, Shukla SS, et al. Polymeric micelles: basic research to clinical practice. Int J Pharm. 2017;532(1):249–68.

    CAS  PubMed  Google Scholar 

  50. 50.

    Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression. Cancer Res. 2002;62(24):7335–42.

    CAS  PubMed  Google Scholar 

  51. 51.

    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14(14):4491–9.

    CAS  PubMed  Google Scholar 

  52. 52.

    Diccianni MB, Chilcote RR, Yu AL. The genes of chromosomes 9p21 (p16, p15, ARF, MTAP) in pediatric acute leukemia: inactivation and exploitation for tumor-targeted therapeutics. Trends Cancer. 2007;2:135–49.

    Google Scholar 

  53. 53.

    Ding B, Yu J, Yu R, Mendez L, Shaknovich R, Zhang Y, et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood. 2007;111(3):1515–23.

    PubMed  Google Scholar 

  54. 54.

    Donnelly RF, Singh TRR, Garland MJ, Migalska K, Majithiya R, Mccrudden CM, et al. Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv Funct Mater. 2012;22(23):4879–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Dragicevic N, Maibach H. Nanocarriers. Percutaneous penetration enhancers chemical methods in penetration enhancement. 1st ed. Berlin: Springer; 2016. p. 384.

    Google Scholar 

  56. 56.

    Drexler I, Antunes E, Schmitz M, Wölfel T, Huber C, Erfle V, et al. Modified vaccinia virus ankara for delivery of human tyrosinase as melanoma-associated antigen: induction of tyrosinase- and melanoma-specific human leukocyte antigen A*0201-restricted cytotoxic T cells in vitro and in vivo. Cancer Res. 1999;59(19):4955.

    CAS  PubMed  Google Scholar 

  57. 57.

    Dubs-Poterszman M, Tocque B, Wasylyk B. MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene. 1995;11(11):2445–9.

    CAS  PubMed  Google Scholar 

  58. 58.

    Ellis LZ, Liu W, Luo Y, Okamoto M, Qu D, Dunn JH, et al. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion. Biochem Biophys Res Commun. 2011;414(3):551–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Ernest U, Chen HY, Xu MJ, Taghipour YD, Asad MHHB, Rahimi R, et al. Anti-cancerous potential of polyphenol-loaded polymeric nanotherapeutics. Molecules. 2018;23(11):E2787. https://doi.org/10.3390/molecules23112787.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Eskandarpour M. Molecular genetics of cutaneous malignant melanoma. Unpublished doctoral dissertation, Karolinka institute, Repoprint AB Stockholm. 2007.

  61. 61.

    Fagotto F, Glück U, Gumbiner BM. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin. Curr Biol. 1998;8(4):181–90. https://doi.org/10.1016/S0960-9822(98)70082-X.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Faiao-Flores F, Quincoces Suarez J, Fruet A, Maria-Engler S, Pardi P, Maria D. Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression. PLoS One. 2015;10(3):e0118702.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Fang J, Hung C, Hwang T, Huang Y. Physicochemical characteristics and in vivo deposition of liposome-encapsulated tea catechins by topical and intratumor administrations. J Drug Target. 2005;13(1):19–27.

    CAS  PubMed  Google Scholar 

  64. 64.

    Fang Y, Bradley M, Cook K, Herrick E, Nicholl M. A potential role for resveratrol as a radiation sensitizer for melanoma treatment. J Surg Res. 2013;183(2):645–53.

    CAS  PubMed  Google Scholar 

  65. 65.

    Farrar MD, Nicolaou A, Clarke KA, Mason S, Massey KA, Dew TP, et al. A randomized controlled trial of green tea catechins in protection against ultraviolet radiation-induced cutaneous inflammation. Am J Clin Nutr. 2015;102(3):608–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    FDA Guidance for Industry. Nonprescription sunscreen drug products—safety and effectiveness data. 2016. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm473464.pdf [Accessed on 19 July 2018].

  67. 67.

    Feng T, Wei Y, Lee RJ, Zhao L. Liposomal curcumin and its application in cancer. Int J Nanomedicine. 2017;12:6027–44. https://doi.org/10.2147/IJN.S132434.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Foster C, Watson A, Kaplinsky J, Kamaly N. Improved targeting of cancers with nanotherapeutics. Methods Mol Biol. 2017;1530:13–37. https://doi.org/10.1007/978-1-4939-6646-2_2.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Freed-Pastor W, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26(12):1268–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003;22(56):9030–40.

    CAS  PubMed  Google Scholar 

  71. 71.

    Friedrich RB, Kann B, Coradini K, Offerhaus HL, Beck RCR, Windbergs M. Skin penetration behavior of lipid-core nanocapsules for simultaneous delivery of resveratrol and curcumin. Eur J Pharm Sci. 2015;78:204–13.

    CAS  PubMed  Google Scholar 

  72. 72.

    Ganesan MG, Weiner ND, Flynn GL, Ho NFH. Influence of liposomal drug entrapment on percutaneous absorption. Int J Pharm. 1984;20(1–2):139–54.

    CAS  Google Scholar 

  73. 73.

    Gatouillat G, Balasse E, Joseph-Pietras D, Morjani H, Madoulet C. Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma. J Cell Biochem. 2010;110(4):893–902.

    CAS  PubMed  Google Scholar 

  74. 74.

    Gharpure KM, Wu SY, Li C, Lopez-Berestein G, Sood AK. Nanotechnology: future of oncotherapy. Clin Cancer Res. 2015;21(14):3121–30. https://doi.org/10.1158/1078-0432.CCR-14-1189.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Gnerre C, Catto M, Leonetti F, Weber P, Carrupt P, Altomare C, et al. Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs. J Med Chem. 2000;43(25):4747–58.

    CAS  PubMed  Google Scholar 

  76. 76.

    Godin B, Touitou E. Ethosomes: new prospects in transdermal delivery. Crit Rev Ther Drug Carrier Syst. 2003;20(1):63–102.

    CAS  PubMed  Google Scholar 

  77. 77.

    Gonzalez-Rodriguez M, Rabasco AM. Charged liposomes as carriers to enhance the permeation through the skin. Expert Opin Drug Deliv. 2011;8(7):857–71.

    CAS  PubMed  Google Scholar 

  78. 78.

    Goya S, Takadate A, Tanaka T, Nakashima F. Synthesis and fluorescent properties of coumarin derivatives as analytical reagents. Yakugaku Zasshi. 1980;100(3):289–94.

    CAS  Google Scholar 

  79. 79.

    Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851.

    CAS  Google Scholar 

  80. 80.

    Grossman D, Altieri DC. Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev. 2001;20(1):3–11.

    CAS  PubMed  Google Scholar 

  81. 81.

    Gugler R, Leschik M, Dengler HJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol. 1975;9(23):229–34.

    CAS  PubMed  Google Scholar 

  82. 82.

    Gui F, Ma W, Cai S, Li X, Tan Y, Zhou C, et al. Preliminary study on molecular mechanism of curcumine anti-mouse melanoma. Pubmed. 2008;31(11):1685–9.

    CAS  Google Scholar 

  83. 83.

    Guo F, Wang J, Ma M, Tan F, Li N. Skin targeted lipid vesicles as novel nano-carrier of ketoconazole: characterization, in vitro and in vivo evaluation. J Mater Sci Mater Med. 2015;26(4):175.

    PubMed  Google Scholar 

  84. 84.

    Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15(1):195–218.

    CAS  PubMed  Google Scholar 

  85. 85.

    Han T, Das DB. Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review. Eur J Pharm Biopharm. 2015;89(5):312–28.

    CAS  PubMed  Google Scholar 

  86. 86.

    Harris Z, Donovan MG, Branco GM, Limesand KH, Burd R. Quercetin as an emerging anti-melanoma agent: a four-focus area therapeutic development strategy. Front Nutr. 2016;3(48).

  87. 87.

    Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. 2007. https://doi.org/10.1016/j.fct.2007.05.015.

  88. 88.

    Hasty P, Christy B. p53 as an intervention target for cancer and aging. Pathobiol Aging Age Relat Dis. 2013;3(1):22702.

    Google Scholar 

  89. 89.

    He Y, Huang J, Sik R, Chignell C, Liu J, Waalkes M. Expression profiling of human keratinocyte response to ultraviolet A: mplications in apoptosis. J Investig Dermatol. 2004;122(2):533–43. https://doi.org/10.1046/j.0022-202x.2003.22123.x.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Heng MCY. In: Heng MCY, editor. Use of curcumin in treatment of psoriasis, inflammation, skin wounds, burns, and eczemas (WO1999042094A1 ed.). US; 1995.

  91. 91.

    Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420(1):25–7.

    CAS  PubMed  Google Scholar 

  92. 92.

    Hu C, Wang Q, Ma C, Xia Q. Non-aqueous self-double-emulsifying drug delivery system: a new approach to enhance resveratrol solubility for effective transdermal delivery. Colloids Surf A Physicochem Eng Asp. 2016;489:360–9.

    CAS  Google Scholar 

  93. 93.

    Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res. 1994;54(22):5841–7.

    CAS  PubMed  Google Scholar 

  94. 94.

    Ijaz S, Akhtar N, Khan MS, Hameed A, Irfan M, Arshad MA, et al. Plant derived anticancer agents: a green approach towards skin cancers. Biomed Pharmacother. 2018 Jul;103:1643–51. https://doi.org/10.1016/j.biopha.2018.04.113.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Inamdar GS, Madhunapantula SV, Robertson GP. Targeting the MAPK pathway in melanoma: why some approaches succeed and other fail; 2010. https://doi.org/10.1016/j.bcp.2010.04.029.

    Google Scholar 

  96. 96.

    Ishida T, Harashima H, Kiwada H. Liposome clearance. Biosci Rep. 2002;22(2):197–224.

    CAS  PubMed  Google Scholar 

  97. 97.

    Ito A, Fujioka M, Yoshida T, Wakamatsu K, Ito S, Yamashita T, et al. 4-S-cysteaminylphenol-loaded magnetite cationic liposomes for combination therapy of hyperthermia with chemotherapy against malignant melanoma. Cancer Sci. 2007;98(3):424–30.

    CAS  PubMed  Google Scholar 

  98. 98.

    Ito A, Matsuoka F, Honda H, Kobayashi T. Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Immunol Immunother. 2004;53(1):26–32.

    CAS  PubMed  Google Scholar 

  99. 99.

    Jain P k, Joshi H. Coumarin: chemical and pharmacological profile. J Appl Pharm Sci. 2012;02(06):236–40.

    Google Scholar 

  100. 100.

    Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, et al. In: Jang M, editor. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes; 1997.

    Google Scholar 

  101. 101.

    Jang S, Atkins M. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol. 2013;14(2):e60–9.

    CAS  PubMed  Google Scholar 

  102. 102.

    Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, et al. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol. 2009;8(1):25–33.

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Johnson ES, Kornbluth S. In: Shenolikar S, editor. Phosphatases driving mitosis: pushing the gas and lifting the brakes: Academic; 2012. https://doi.org/10.1016/B978-0-12-396456-4.00008-0.

  104. 104.

    Jordan WC, Drew CR. Curcumin—a natural herb with anti-HIV activity. J Natl Med Assoc. 1996;88(6):333.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Jose A, Labala S, Ninave K, Gade S, Venuganti V. Effective skin cancer treatment by topical co-delivery of curcumin and STAT3 siRNA using cationic liposomes. AAPS PharmSciTech. 2017;19(1):166–75.

    PubMed  Google Scholar 

  106. 106.

    Jou PC, Tomecki KJ. Sunscreens in the United States: current status and future outlook. Adv Exp Med Biol. 2014;810:464–84.

    PubMed  Google Scholar 

  107. 107.

    Katiyar S, Mukhtar H. Tea in chemoprevention of cancer. Int J Oncol. 1996;8(2):221–38.

    CAS  PubMed  Google Scholar 

  108. 108.

    Kaur A, Webster MR, Weeraratna AT. In the wnt-er of life: Wnt signalling in melanoma and ageing. Br J Cancer. 2016;215(11):1273–1273–1279.

    Google Scholar 

  109. 109.

    Kaushik G, Ramalingam S, Subramaniam D, Rangarajan P, Protti P, Rammamoorthy P, et al. Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells. Am J Surg. 2012;204(6):868–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Kenessey I, Keszthelyi M, Kramer Z, Berta J, Adam A, Dobos J e a. Inhibition of c-met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma. Curr Cancer Drug Targets. 2010;10(3):332–42.

    CAS  PubMed  Google Scholar 

  111. 111.

    Khuda-Bukhsh A, Bhattacharyya SS, Paul S, Boujedaini N. Polymeric nanoparticle encapsulation of a naturally occurring plant scopoletin and its effects on human melanoma cell A375. J Chin Integr Med. 2010;8(9):853.

    CAS  Google Scholar 

  112. 112.

    Kitagawa S, Kasamaki M. Enhanced delivery of retinoic acid to skin by cationic liposomes. Chem Pharm Bull. 2006;54(2):242–4.

    CAS  PubMed  Google Scholar 

  113. 113.

    Kohn AD, Moon RT. Wnt and calcium signaling: β-catenin-independent pathways; 2005. https://doi.org/10.1016/j.ceca.2005.06.022.

    Google Scholar 

  114. 114.

    Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4(2):68–75.

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Kostova I. Synthetic and natural coumarins as cytotoxic agents. Curr Med Chem AntiCancer Agents. 2005;5(1):29–46.

    CAS  PubMed  Google Scholar 

  116. 116.

    Kumar A, Ahuja A, Ali J, Baboota S. Conundrum and therapeutic potential of curcumin in drug deliveryrapeutic. Crit Rev Ther Drug Carrier Syst. 2010;27(4):279–312.

    CAS  PubMed  Google Scholar 

  117. 117.

    Kumari A, Yadav SK, Pakade YB, Singh B, Yadav SC. Development of biodegradable nanoparticles for delivery of quercetin. Colloids Surf B: Biointerfaces. 2010;80(2):184–92.

    CAS  PubMed  Google Scholar 

  118. 118.

    Kumari P, Muddineti OS, Rompicharla SVK, Ghanta P, A Karthik BBN, Ghosh B, et al. Cholesterol-conjugated poly(D, L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy. Drug Deliv. 2017;24(1):209–23.

    CAS  PubMed  Google Scholar 

  119. 119.

    Kumari P, Swami MO, Nadipalli SK, Myneni S, Ghosh B, Biswas S. Curcumin delivery by poly(lactide)-based co-polymeric micelles: an in vitro anticancer study. Pharm Res. 2016;33(4):826–41.

    CAS  PubMed  Google Scholar 

  120. 120.

    Kurzrock R, Li L, Mehta K, Aggarawal BB. University of Texas System (Ed.), Liposomal curcumin for treatment of cancer (US7968115B2 ed.). US; 2004.

  121. 121.

    Kuttan R, Bhanumathy P, Nirmala K, George M. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett. 1985;29(2):197–202.

    CAS  PubMed  Google Scholar 

  122. 122.

    Kwatra S, Taneja G, Nasa N. Alternative routes of drug administration- transdermal, pulmonary & parenteral. Indo Global J Pharm Sci. 2012;2(4):409–26.

    Google Scholar 

  123. 123.

    Lapteva M, Mondon K, MÃller M, Gurny R, Kalia YN. Polymeric micelle nanocarriers for the cutaneous delivery of tacrolimus: a targeted approach for the treatment of psoriasis. Mol Pharm. 2014;11(9):2989–3001.

    CAS  PubMed  Google Scholar 

  124. 124.

    Lee J, Jang J, Park C, Kim B, Choi Y, Choi B. Curcumin suppresses α-melanocyte stimulating hormone-stimulated melanogenesis in B16F10 cells. Int J Mol Med. 2010;26(1):101–6.

    PubMed  Google Scholar 

  125. 125.

    Lee W. Tumor suppressor genes—the hope. FASEB J. 1993;7(10):819.

    CAS  PubMed  Google Scholar 

  126. 126.

    Lee W, Shim J, Zhu B. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol. 2005;68(4):1018–30.

    CAS  PubMed  Google Scholar 

  127. 127.

    Legha SS, Ring S, Papadopoulos N, Plager C, Chawla S, Benjamin R. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer. 1989;64(10):2024–9.

    CAS  PubMed  Google Scholar 

  128. 128.

    Lei M, Dong Y, Sun C, Zhang X. Resveratrol inhibits proliferation, promotes differentiation and melanogenesis in HT-144 melanoma cells through inhibition of MEK/ERK kinase pathway. Microb Pathog. 2017;111:410–3. https://doi.org/10.1016/j.micpath.2017.09.029.

    CAS  Article  PubMed  Google Scholar 

  129. 129.

    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31.

    CAS  PubMed  Google Scholar 

  130. 130.

    Levine A, Momand J, Finlay C. The p53 tumour suppressor gene. Nature. 1991;351(6326):453–6.

    CAS  PubMed  Google Scholar 

  131. 131.

    Levy DE, Darnell JE. Signalling: stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.

    CAS  PubMed  Google Scholar 

  132. 132.

    Li L, Wu L, Jiang Y, Tashiro S, Onodera S, Uchiumi F, et al. Silymarin enhanced cytotoxic effect of anti-fas agonistic antibody CH11 on A375-S2 cells. J Asian Nat Prod Res. 2007;9(7):593–602.

    PubMed  Google Scholar 

  133. 133.

    Li PF, Dietz R, von Harsdorf R. p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by bcl-2. EMBO J. 1999;18(21):6027–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Lin YH, Tsai MJ, Fang YP, Fu YS, Huang YB, Wu PC. Microemulsion formulation design and evaluation for hydrophobic compound: catechin topical application. Colloids Surf B: Biointerfaces. 2018;161:121–8. https://doi.org/10.1016/j.colsurfb.2017.10.015.

    CAS  Article  PubMed  Google Scholar 

  135. 135.

    Linden K, Meyskens F. Session 7 S21. Chemoprevention of non-melanoma skin cancer: experience with a polyphenol from green tea. Eur J Cancer. 2002;38:S24.

    Google Scholar 

  136. 136.

    Liu G, Zhang Z, Yang B, He W. Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice; 2012. https://doi.org/10.1016/j.lfs.2012.08.033.

    Google Scholar 

  137. 137.

    Liu J, Chen S, Lin C, Tsai S, Liang Y. Inhibition of melanoma growth and metastasis by combination with (−)-epigallocatechin-3-gallate and dacarbazine in mice. J Cell Biochem. 2001;83(4):631–42.

    CAS  PubMed  Google Scholar 

  138. 138.

    Loch-Neckel G, Santos-Bubniak L, Mazzarino L, Jacques AV, Moccelin B, Santos-Silva M, et al. Orally administered chitosan-coated polycaprolactone nanoparticles containing curcumin attenuate metastatic melanoma in the lungs. J Pharm Sci. 2015;104(10):3524–34.

    CAS  PubMed  Google Scholar 

  139. 139.

    Losa G. Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. Eur J Clin Investig. 2003;33(9):818–23.

    CAS  Google Scholar 

  140. 140.

    Lui P, Cashin R, Machado M, Hemels M, Corey-Lisle P, Einarson TR. Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 33(8):665–80.

  141. 141.

    Ma Z, Molavi O, Haddadi A, Lai R, Gossage R, Lavasanifar A. Resveratrol analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) mediates anti-tumor effects via mechanism different from that of resveratrol. Cancer Chemother Pharmacol. 2008;63(1):27–35.

    CAS  PubMed  Google Scholar 

  142. 142.

    Madronich S, McKenzie R, Björn L, Caldwell M. Changes in biologically active ultraviolet radiation reaching the Earth’s surface. J Photochem Photobiol B Biol. 1998;46(1–3):5–19. https://doi.org/10.1016/s1011-1344(98)00182-1.

    CAS  Article  Google Scholar 

  143. 143.

    Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273(22):13375–8.

    CAS  PubMed  Google Scholar 

  144. 144.

    Makhmalzade B, Chavoshy F. Polymeric micelles as cutaneous drug delivery system in normal skin and dermatological disorders. J Adv Pharm Technol Res. 2018;(1):2.

  145. 145.

    Malhotra U, Zaidi AH, Kosovec JE, Kasi P, Komatsu Y, Rotoloni CL, et al. Prognostic value and targeted inhibition of survivin expression in esophageal adenocarcinoma and cancer-adjacent squamous epithelium. PLoS One. 2013;8(11):e78343.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Mangalathillam S, Rejinold NS, Nair A, Lakshmanan VK, Nair SV, Jayakumar R. Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route. Nanoscale. 2012;4(1):239–50. https://doi.org/10.1039/c1nr11271f.

    CAS  Article  PubMed  Google Scholar 

  147. 147.

    Marin YE a, Wall BA a, Wang S a, Namkoong J a, Martino JJ a, Suh J b c, et al. Curcumin downregulates the constitutive activity of NF-κB and induces apoptosis in novel mouse melanoma cells. Melanoma Res. 2007;17(5):274–83.

    CAS  PubMed  Google Scholar 

  148. 148.

    Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P, et al. Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br J Cancer. 2013;109(2):433.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Mazumder A, Raghavan K, Weinstein J, Kohn KW, Pommier Y. Inhibition of humanimmunodeficiency virus type-1 integrase by curcumin; 1995. https://doi.org/10.1016/0006-2952(95)98514-A.

    Google Scholar 

  150. 150.

    Mazzarino L, Otsuka I, Halila S, Bubniak L d S, Mazzucco S, Santos-Silva M, et al. Xyloglucan-block-poly(ϵ-caprolactone) copolymer nanoparticles coated with chitosan as biocompatible mucoadhesive drug delivery system. Macromol Biosci. 2014;14(5):709–19.

    CAS  PubMed  Google Scholar 

  151. 151.

    McCook JP, Persaud I, Narain NR. Topical formulations having enhanced bioavailability. 2012 US12/052,825, 2013 US13/751,769.

  152. 152.

    McKibbin T. Melanoma: understanding relevant molecular pathways as well as available and emerging therapies. AJMC Peer Exchange. 2015;21:224–33.

    Google Scholar 

  153. 153.

    Meghana PC, Hardik PH, Rajnikant SM, Sandip PR. Liposomes: as a topical drug delivery system. Int J Pharm Chem Sci. 2012;(1):1.

  154. 154.

    Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001;47(2):165–96.

    CAS  PubMed  Google Scholar 

  155. 155.

    Metodiewa D, Jaiswal AK, Cenas N, Dickancaité E, Segura-Aguilar J. Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free Radic Biol Med. 1999;26(1):107–16. https://doi.org/10.1016/S0891-5849(98)00167-1.

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    Minamimura T, Sato H, Kasaoka S, Saito T, Ishizawa S, Takemori S, et al. Tumor regression by inductive hyperthermia combined with hepatic embolization using dextran magnetite-incorporated microspheres in rats. Int J Oncol. 2000:1153–61.

  157. 157.

    Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei H, et al. Curcumin: a new candidate for melanoma therapy? Int J Cancer. 2016;139(8):1683–95.

    CAS  PubMed  Google Scholar 

  158. 158.

    Mooney E, Ruis Peris J, O'Neill A, Sweeney E. Apoptotic and mitotic indices in malignant melanoma and basal cell carcinoma. J Clin Pathol. 1995;48(3):242–4. https://doi.org/10.1136/jcp.48.3.242.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Morris V, Toseef T, Nazumudeen F, Rivoira C, Spatafora C, Tringali C, et al. Anti-tumor properties of cis-resveratrol methylated analogues in metastatic mouse melanoma cells. Mol Cell Biochem. 2014;402(1–2):83–91.

    Google Scholar 

  160. 160.

    Mozuraitiene J, Bielskiene K, Atkocius V, Labeikyte D. Molecular alterations in signal pathways of melanoma and new personalized treatment strategies: targeting of notch; 2015. https://doi.org/10.1016/j.medici.2015.06.002.

    Google Scholar 

  161. 161.

    Murota K, Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism; 2003. https://doi.org/10.1016/S0003-9861(03)00284-4.

    Google Scholar 

  162. 162.

    Nagula R, Wairkar S. Recent advances in topical delivery of flavonoids: a review. J Control Release. 2019;296:190–201. https://doi.org/10.1016/j.jconrel.2019.01.029.

    CAS  Article  PubMed  Google Scholar 

  163. 163.

    Narasipura SD, Henderson LJ, Fu SW, Chen L, Kashanchi F, Al-Harthi L. Role of β-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes. J Virol. 2012;86(4):1911–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    National Center for Biotechnology Information. PubChem Compound Database; CID=445154, https://pubchem.ncbi.nlm.nih.gov/compound/445154 (accessed 17 Feb 2019).

  165. 165.

    National Center for Biotechnology Information. PubChem Compound Database; CID=969516, https://pubchem.ncbi.nlm.nih.gov/compound/969516 (accessed 17 Feb 2019).

  166. 166.

    National Center for Biotechnology Information. PubChem Compound Database; CID=5280343, https://pubchem.ncbi.nlm.nih.gov/compound/5280343 (accessed 17 Feb 2019).

  167. 167.

    Naves LB, Dhand C, Venugopal JR, Rajamani L, Ramakrishna S, Almeida L. Nanotechnology for the treatment of melanoma skin cancer. Prog Biomater. 2017;6(1):13–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Nguyen TA, Friedman AJ. Curcumin: a novel treatment for skin-related disorders. J Drugs Dermatol. 2013;12(10):1131–7.

    CAS  PubMed  Google Scholar 

  169. 169.

    Nihal M, Ahmad N, Mukhtar H, Wood G. Anti-proliferative and proapoptotic effects of (?)-epigallocatechin-3-gallate on human melanoma: possible implications for the chemoprevention of melanoma. Int J Cancer. 2005;114(4):513–21.

    CAS  PubMed  Google Scholar 

  170. 170.

    Niles R, McFarland M, Weimer M, Redkar A, Fu Y, Meadows G. Resveratrol is a potent inducer of apoptosis in human melanoma cells. Cancer Lett. 2003;190(2):157–63.

    CAS  PubMed  Google Scholar 

  171. 171.

    Nitta M, Azuma K, Hata K, Takahashi S, Ogiwara K, Tsuka T, et al. Systemic and local injections of lupeol inhibit tumor growth in a melanoma-bearing mouse model. Biomed Rep. 2013;1(4):641–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Oelkrug C, Lange CM, Wenzel E, Fricke S, Hartke M, Simasi J, et al. Analysis of the tumoricidal and anti-cachectic potential of curcumin. Anticancer Res. 2014;34(9):4781–8.

    CAS  PubMed  Google Scholar 

  173. 173.

    Okamoto T. Safety of quercetin for clinical application (review). Int J Mol Med. 2005;16(2):275–8.

    CAS  PubMed  Google Scholar 

  174. 174.

    Orgaz JL, Sanz-Moreno V. Emerging molecular targets in melanoma invasion and metastasis. Pigment Cell Melanoma Res. 2013;26(1):39–57.

    CAS  PubMed  Google Scholar 

  175. 175.

    Orlow I, Begg CB, Cotignola J, Roy P, Hummer AJ, Clas BA, et al. CDKN2A germline mutations in individuals with cutaneous malignant melanoma; 2007. https://doi.org/10.1038/sj.jid.5700689.

    Google Scholar 

  176. 176.

    Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W. Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J. 2005;392:249.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Osmond G, Augustine C, Zipfel P, Padussis J, Tyler D. Enhancing melanoma treatment with resveratrol. J Surg Res. 2012;172(1):109–109-15.

    CAS  PubMed  Google Scholar 

  178. 178.

    Ossio R, Roldán-Marín R, Martínez-Said H, Adams DJ, Robles-Espinoza CD. Melanoma: a global perspective. Nat Rev Cancer. 2017:393–4. https://doi.org/10.1038/nrc.2017.43.

  179. 179.

    Pal HC, Sharma S, Strickland LR, Katiyar SK, Ballestas ME, Athar M, et al. Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFkappaB signaling pathways.(research article). PLoS One. 2014;9(1):e86338.

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Palmieri G, Colombino M, Sini MC, Ascierto PA, Lissia A, Cossu A. Duc GHT, editor. Targeted therapies in melanoma: successes and pitfalls: InTech.

  181. 181.

    Paluncic, J., Kovacevic, Z., Jansson, P. J., Kalinowski, D., Merlot, A. M., Huang, M. L.et al. (2016). Roads to melanoma: key pathways and emerging players in melanoma progression and oncogenic signaling https://doi-org.cuhsl.creighton.edu/10.1016/j.bbamcr.2016.01.025.

  182. 182.

    Panayi ND, Mendoza EE, Breshears ES, Burd R. In: Davids LM, editor. Aberrant death pathways in melanoma: InTech; 2013.

  183. 183.

    Pando D, Caddeo C, Manconi M, Fadda AM, Pazos C. Nanodesign of olein vesicles for the topical delivery of the antioxidant resveratrol. J Pharm Pharmacol. 2013;65(8):1158–67.

    CAS  PubMed  Google Scholar 

  184. 184.

    Pezzuto JM, Moon RC, Jang MS, Ouali A, Lin S, Barillas KS. In: Pharmascience Inc, editor. Pharmaceutical formulations of resveratrol and methods of use thereof (US6414037B1 ed.). US; 1998.

  185. 185.

    Piepkorn M. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol. 2000;42(5, Part 1):705–26 https://doi-org.cuhsl.creighton.edu/10.1067/mjd.2000.104687.

    CAS  PubMed  Google Scholar 

  186. 186.

    Ploper D, De Robertis EM. The MITF family of transcription factors: role in endolysosomal biogenesis, wnt signaling, and oncogenesis; 2015. https://doi.org/10.1016/j.phrs.2015.04.006.

    Google Scholar 

  187. 187.

    Propper DJ, Braybrooke JP, Levitt NC, O'Byrne K, Christodoulos K, Han C, et al. Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine. Br J Cancer. 2000;82(11):1759–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Pun SH, Tack F, Bellocq NC, Cheng J, Grubbs BH, Jensen GS, et al. Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles. Cancer Biol Ther. 2004;3(7):641–50.

    CAS  PubMed  Google Scholar 

  189. 189.

    Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, et al. c-met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res. 2007;13(7):2246–53. https://doi.org/10.1158/1078-0432.CCR-06-0776.

    CAS  Article  PubMed  Google Scholar 

  190. 190.

    Qiu S, Tan S, Zhang JA, Liu A, Yuan JY, Rao GZ, et al. Apoptosis induced by curcumin and its effect on c-myc and caspase-3 expressions in human melanoma A375 cell line. 2005;25(12):1517–21.

  191. 191.

    Ramalingam P, Ko YT. Enhanced oral delivery of curcumin from N-trimethyl chitosan surface-modified solid lipid nanoparticles: pharmacokinetic and brain distribution evaluations. Pharm Res. 2015;32(2):389–402.

    CAS  PubMed  Google Scholar 

  192. 192.

    Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006;106(2):375–82.

    CAS  PubMed  Google Scholar 

  193. 193.

    Rastrelli M, Tropea S, Rossi CR, Alaibac M. Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification. In Vivo. 2014;28(6):1005–11.

    PubMed  Google Scholar 

  194. 194.

    Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology. 1980;16(3):259–65.

    CAS  PubMed  Google Scholar 

  195. 195.

    Ravindranath, M. H., Ramasamy, V., Moon, S., Ruiz, C., & Muthugounder, S. Differential growth suppression of human melanoma cells by tea (camellia sinensis) epicatechins (ECG, EGC and EGCG). Evidence-Based Complementary and Alternative Medicine, (2009);6(4):523–530.

  196. 196.

    Raza K, Singh B, Lohan S, Sharma G, Negi P, Yachha Y, et al. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Int J Pharm. 2013;456(1):65–72. https://doi.org/10.1016/j.ijpharm.2013.08.019.

    CAS  Article  PubMed  Google Scholar 

  197. 197.

    Rigon RB, Oyafuso MH, Fujimura AT, Gonçalez ML, do Prado AH, Gremião M, et al. Nanotechnology-based drug delivery systems for melanoma antitumoral therapy: a review. Biomed Res Int. 2015;2015:841817.

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Riley PA, Cooksey CJ, Johnson CI, Land EJ, Latter AM, Ramsden CA. Melanogenesis-targeted anti-melanoma pro-drug development: effect of side-chain variations on the cytotoxicity of tyrosinase-generated ortho-quinones in a model screening system. Eur J Cancer. 1997;33(1):135–43.

    CAS  PubMed  Google Scholar 

  199. 199.

    Ritchie, H., & Roser, M. (2019). Ozone layer. Retrieved from https://ourworldindata.org/ozone-layer

    Google Scholar 

  200. 200.

    Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Oncogene. 2012;31(39):4257.

    CAS  PubMed  Google Scholar 

  201. 201.

    Robinson, M. J., & Cobb, M. H. (1997). Mitogen-activated protein kinase pathways https://doi.org/10.1016/S0955-0674(97)80061-0.

  202. 202.

    Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17(3):330–9.

    PubMed  Google Scholar 

  203. 203.

    Ruel-Gariépy E, Leroux J. In situ-forming hydrogels—review of temperature-sensitive systems; 2004. https://doi.org/10.1016/j.ejpb.2004.03.019.

    Google Scholar 

  204. 204.

    Sabbatino F, Wang Y, Wang X, Ferrone S, Ferrone C. Emerging BRAF inhibitors for melanoma. Expert Opin Emerging Drugs. 2013;18(4):431–43.

    CAS  Google Scholar 

  205. 205.

    Saha RN, Vasanthakumar S, Bende G, Snehalatha M. Nanoparticulate drug delivery systems for cancer chemotherapy. Mol Membr Biol. 2010;27(7):215–31.

    CAS  PubMed  Google Scholar 

  206. 206.

    Sahebkar A. Dual effect of curcumin in preventing atherosclerosis: the potential role of pro-oxidant–antioxidant mechanisms. Nat Prod Res. 2014;29(6):491–2.

    PubMed  Google Scholar 

  207. 207.

    Sahoo NG, Kakran M, Shaal LA, Li L, Müller RH, Pal M, et al. Preparation and characterization of quercetin nanocrystals. J Pharm Sci. 2011;100(6):2379–90.

    CAS  Google Scholar 

  208. 208.

    Sahu S, Saraf S, Kaur C, Saraf S. Biocompatible nanoparticles for sustained topical delivery of anticancer phytoconstituent quercetin. Pak J Biol Sci. 2013;16(13):601–9.

    CAS  PubMed  Google Scholar 

  209. 209.

    Saitoh K, Takahashi H, Sawada N, Parsons P. Detection of the c-met proto-oncogene product in normal skin and tumours of melanocytic origin. J Pathol. 1994;174(3):191–9. https://doi.org/10.1002/path.1711740308.

    CAS  Article  PubMed  Google Scholar 

  210. 210.

    Sala M, Diab R, Elaissari A, Fessi H. Lipid nanocarriers as skin drug delivery systems: properties, mechanisms of skin interactions and medical applications. Int J Pharm. 2018;535(1–2):1–17. https://doi.org/10.1016/j.ijpharm.2017.10.046.

    CAS  Article  PubMed  Google Scholar 

  211. 211.

    Saleem M, Maddodi N, Abu Zaid M, Khan N, Bin Hafeez B, Asim M, et al. Lupeol inhibits growth of highly aggressive human metastatic melanoma cells in vitro and in vivo by inducing apoptosis. Clin Cancer Res. 2008;14(7):2119.

    CAS  PubMed  Google Scholar 

  212. 212.

    Sanidad K, Zhu J, Wang W, Du Z, Zhang G. Effects of stable degradation products of curcumin on cancer cell proliferation and inflammation. J Agric Food Chem. 2016;64(48):9189–95.

    CAS  PubMed  Google Scholar 

  213. 213.

    Sarkar D, Leung EY, Baguley BC, Finlay GJ, Askarian-Amiri M. Epigenetic regulation in human melanoma: past and future. Epigenetics. 2015;10(2):103–21.

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Sarkar S, Horn G, Moulton K, Oza A, Byler S, Kokolus S, et al. Cancer development, progression, and therapy: an epigenetic overview. Basel: MDPI AG; 2013.

    Google Scholar 

  215. 215.

    Scognamiglio I, De Stefano D, Campani V, Mayol L, Carnuccio R, Fabbrocini G, et al. Nanocarriers for topical administration of resveratrol: a comparative study. Int J Pharm. 2012;440(2).

  216. 216.

    Sharma O. Antioxidant activity of curcumin and related compounds. Biochem Pharmacol. 1976;25(15):1811–2.

    CAS  PubMed  Google Scholar 

  217. 217.

    Sharma V, Kumar L, Mohanty SK, Maikhuri JP, Rajender S, Gupta G. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor—synergistic action of quercetin and curcumin. Mol Cell Endocrinol. 2016;431:12–23.

    CAS  PubMed  Google Scholar 

  218. 218.

    Shashanka R, Smitha B. Head and neck melanoma. ISRN Surg. 2012;2012:1–7. https://doi.org/10.5402/2012/948302.

    Article  Google Scholar 

  219. 219.

    Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19(19):5320–8. https://doi.org/10.1158/1078-0432.CCR-13-0259.

    CAS  Article  PubMed  Google Scholar 

  220. 220.

    Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas P. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64(04):353–6.

    CAS  Google Scholar 

  221. 221.

    Siddiqui IA, Bharali DJ, Nihal M, Adhami VM, Khan N, Chamcheu JC, et al. Excellent anti-proliferative and pro-apoptotic effects of (−)-epigallocatechin-3-gallate encapsulated in chitosan nanoparticles on human melanoma cell growth both in vitro and in vivo; 2014. https://doi.org/10.1016/j.nano.2014.05.007.

    Google Scholar 

  222. 222.

    Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications; 2011. https://doi.org/10.1016/j.bcp.2011.07.093.

    Google Scholar 

  223. 223.

    Singh T, Katiyar SK. Green tea catechins reduce invasive potential of human melanoma cells by targeting COX-2, PGE(2) receptors and epithelial-to-mesenchymal transition. PLoS One. 2011;6(10):e25224.

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase and nuclear factor κB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the akt pathway. Cancer. 2005;104(4):879–90.

    CAS  PubMed  Google Scholar 

  225. 225.

    Smejkalova D., Muthný, T., Nešporová, K., Hermannová, M., Achbergerová, E., Huerta-Angeles, G., et al.(2017). Hyaluronan polymeric micelles for topical drug delivery. https://doi-org.cuhsl.creighton.edu/10.1016/j.carbpol.2016.09.013.

    Google Scholar 

  226. 226.

    Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene. 2003;22(20):3138–51.

    CAS  PubMed  Google Scholar 

  227. 227.

    Steinhusen U, Badock V, Bauer A, Behrens J, Wittman-Liebold B, Dörken B, et al. Apoptosis-induced cleavage of β-catenin by caspase-3 results in proteolytic fragments with reduced transactivation potential. J Biol Chem. 2000;275(21):16345–53.

    CAS  PubMed  Google Scholar 

  228. 228.

    Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, et al. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science. 2002;295(5562):2088–91.

    CAS  PubMed  Google Scholar 

  229. 229.

    Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17(17):5001–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Strickland L, Pal H, Elmets C, Afaq F. Targeting drivers of melanoma with synthetic small molecules and phytochemicals. Cancer Lett. 2015;359(1):20–35. https://doi.org/10.1016/j.canlet.2015.01.016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Sun R, Zhao G, Xia Q. Lipid based nanocarriers with different lipid compositions for topical delivery of resveratrol: comparative analysis of characteristics and performance. J Drug Deliv Sci Technol. 2014a;24(6):591–600.

    CAS  Google Scholar 

  232. 232.

    Sun, Y., Du, L., Liu, Y., Li, X., Li, M., Jin, Y., et al.(2014b). Transdermal delivery of the in-situ hydrogels of curcumin and its inclusion complexes of hydroxypropyl-β-cyclodextrin for melanoma treatment. https://doi-org.cuhsl.creighton.edu/10.1016/j.ijpharm.2014.04.039.

  233. 233.

    Surriga O, Rajasekhar VK, Ambrosini G, Dogan Y, Huang R, Schwartz GK. Crizotinib, a c-met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther. 2013;12(12):2817.

    CAS  PubMed  Google Scholar 

  234. 234.

    Syed D, Afaq F, Maddodi N, Johnson J, Sarfaraz S, Ahmad A, et al. 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(6):1291–9.

    CAS  PubMed  Google Scholar 

  235. 235.

    Tan Q, Liu W, Guo C, Zhai G. Preparation and evaluation of quercetin-loaded lecithin-chitosan nanoparticles for topical delivery. Int J Nanomed. 2011;6:1621–30.

    CAS  Google Scholar 

  236. 236.

    Tang Y, Lin R, Tsai Y, Hsu H, Yang Y, Chen C, et al. MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer. Clin Cancer Res. 2012;18(16):4325.

    CAS  PubMed  Google Scholar 

  237. 237.

    Tarapore RS, Siddiqui IA, Saleem M, Adhami VM, Spiegelman VS, Mukhtar H. Specific targeting of wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol. Carcinogenesis. 2010;31(10):1844–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238.

    Thangasamy T, Sittadjody SH, Limesand K, Burd R. Tyrosinase overexpression promotes ATM-dependent p53 phosphorylation by quercetin and sensitizes melanoma cells to dacarbazine. Cell Oncol. 2008;30(5):371–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Thangasamy T, Sittadjody S, Lanza-Jacoby S, Wachsberger P, Limesand K, Burd R. Quercetin selectively inhibits bioreduction and enhances apoptosis in melanoma cells that overexpress tyrosinase. Nutr Cancer. 2007;59(2):258–68.

    CAS  PubMed  Google Scholar 

  240. 240.

    Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, et al. Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical wnt/β-catenin pathway. ACS Nano. 2014;8(1):76.

    CAS  PubMed  Google Scholar 

  241. 241.

    Tortora GJ, Derrickson B. Principles of anatomy & physiology. 14th ed. Hoboken: Wiley; 2014.

    Google Scholar 

  242. 242.

    Tyagi YK, Kumar A, Raj HG, Vohra P, Gupta G, Kumari R, et al. Synthesis of novel amino and acetyl amino-4-methylcoumarins and evaluation of their antioxidant activity; 2005. https://doi.org/10.1016/j.ejmech.2004.09.002.

    Google Scholar 

  243. 243.

    Ugurel S, Paschen A, Becker JC. Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent. J Invest Dermatol. 2013;133(2):289–92. https://doi.org/10.1038/jid.2012.341.

    CAS  Article  PubMed  Google Scholar 

  244. 244.

    Vargas, A., & Burd, R. (2010). Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutrition Reviews, 68(7), 418–428.

  245. 245.

    Verma DD, Verma S, Blume G, Fahr A. Particle size of liposomes influences dermal delivery of substances into skin; 2003. https://doi.org/10.1016/S0378-5173(03)00183-2.

    Google Scholar 

  246. 246.

    Vogt PK, Hart JR. PI3K and STAT3: a new alliance. Cancer Discov. 2011;1(6):481–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    Volkovova K, Bilanicova D, Bartonova A, Letašiová S, Dusinska M. (2012). Associations between environmental factors and incidence of cutaneous melanoma. Review. Environ Health, 11(Suppl 1), S12.

  248. 248.

    Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer. 2002;2(8):594–604.

    CAS  PubMed  Google Scholar 

  249. 249.

    Wang B, Liu X, Teng Y, Yu T, Chen J, Hu Y, et al. Improving anti-melanoma effect of curcumin by biodegradable nanoparticles. Oncotarget. 2017;8(65):108624–42. https://doi.org/10.18632/oncotarget.20585.

    Article  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Wang M, Yu T, Zhu C, Sun H, Qiu Y, Zhu X, et al. Resveratrol triggers protective autophagy through the ceramide/Akt/mTOR pathway in melanoma B16 cells. Nutr Cancer. 2014;66(3):435–40.

    CAS  PubMed  Google Scholar 

  251. 251.

    Watjen W, Michels G, Steffan B, Niering P, Chovolou Y, Kampkötter A, et al. Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J Nutr. 2005;135(3):525–31.

  252. 252.

    Weinberg R. Tumor suppressor genes. Science (Washington). 1991;254(5035):1138–46.

    CAS  Google Scholar 

  253. 253.

    World Health Organization, Solar ultraviolet radiation: global burden of disease from solar ultraviolet radiation. Environmental Burden of Disease Series, N.13. 2006.

  254. 254.

    World Health Organization; Ultraviolet radiation (UV): skin cancers. 2019, from https://www.who.int/uv/faq/skincancer/en/index1.html

  255. 255.

    Yajima I, Kumasaka M, Thang N, Goto Y, Takeda K, Yamanoshita O, et al. RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling in malignant melanoma progression and therapy. Dermatol Res Pract. 2012;354191.

  256. 256.

    Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer. 2009;9(6):429.

    CAS  PubMed  PubMed Central  Google Scholar 

  257. 257.

    Yeh M, Chen C, Hsieh D, Huang K, Chan Y, Hong P, et al. Improving anticancer efficacy of (−)-epigallocatechin-3-gallate gold nanoparticles in murine B16F10 melanoma cells. Drug Des Devel Ther. 2014;8:459–74.

    PubMed  PubMed Central  Google Scholar 

  258. 258.

    Yi Z, Li L, Matsushima GK, Earp HS, Wang B, Tisch R. A novel role for c-src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells. Blood. 2009;114(15):3191.

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259.

    Zhang G, Miura Y, Yagasaki K. Induction of apoptosis and cell cycle arrest in cancer cells by in vivo metabolites of teas. Nutr Cancer. 2000;38(2):265–27.

    CAS  PubMed  Google Scholar 

  260. 260.

    Zhang Y, Li Y, Lv Y, Wang J. Effect of curcumin on the proliferation, apoptosis, migration, and invasion of human melanoma A375 cells. Genet Mol Res. 2015;14(1):1056–67.

    CAS  PubMed  Google Scholar 

  261. 261.

    Zhao, L., Li, Y., He, M., Song, Z., Lin, S., Yu, Z., et al. (2014). The fanconi anemia pathway sensitizes to DNA alkylating agents by inducing JNK-p53-dependent mitochondrial apoptosis in breast cancer cells.

    Google Scholar 

  262. 262.

    Zheng N, Wang J, Yang S, Wu J. Aberrant epigenetic alteration in Eca9706 cells modulated by nanoliposomal quercetin combined with butyrate mediated via epigenetic-NF-κB signaling. Asian Pac J Cancer Prev. 2014;15(11):4539.

    PubMed  Google Scholar 

  263. 263.

    Zhu X, Zeng X, Zhang X, Cao W, Wang Y, Chen H, et al. The effects of quercetin-loaded PLGA-TPGS nanoparticles on ultraviolet B-induced skin damages in vivo; 2016. https://doi.org/10.1016/j.nano.2015.10.016.

    Google Scholar 

  264. 264.

    Zlotogorski, A., Dayan, A., Dayan, D., Chaushu, G., Salo, T., & Vered, M. (2013). Nutraceuticals as new treatment approaches for oral cancer—I: curcumin. https://doi-org.cuhsl.creighton.edu/10.1016/j.oraloncology.2012.09.015.

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Heenatigala Palliyage, G., Singh, S., Ashby, C.R. et al. Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma. AAPS PharmSciTech 20, 250 (2019). https://doi.org/10.1208/s12249-019-1457-1

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KEY WORDS

  • melanoma
  • polyphenol
  • topical
  • transdermal delivery
  • poor solubility
  • curcumin
  • resveratrol
  • quercetin
  • chemoprevention