Abstract
Genistein (Gen), a major soy isoflavone, produces extensive pro-apoptotic anticancer effects, mediated predominantly via induction of mitochondrial damage. Based on several biophysical model criteria, our rational assumptions for the native mitochondrial selectivity of Gen allowed its design as a cationic lipid-based nanocarrier (NC) system. Proof-of-concept nano-formulations, lipidic micelles (Mic), and nanoemulsions (NEs) incorporated Gen, which serves as therapeutic and targeting moieties, specific for mitochondria. Our in vitro experimental data demonstrated superior physicochemical properties and significant cytotoxicity of Gen-NCs (five- to tenfolds lower EC50) compared to all drug controls, in hepatic and colon carcinomas. The established mitochondria-specific accumulation of the various Gen-NCs positively correlated with marked mitochondrial depolarization effects. Within first 24 h, Gen-NC treatments ultimately lead to distinct activation of intrinsic apoptotic pathway markers, such as cytosolic cytochrome c and specific caspase-9 vs. nonspecific caspases-3, 7, and 8. Such mechanistic evidence of the mitochondriotropic activity of our Gen-NC platforms favors their prospective as intracellularly targeted delivery nano-vehicles, to enhance anticancer efficacy of different co-formulated chemotherapeutic agents.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Costantini P, Jacotot E, Decaudin D, Kroemer G (2000) Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92:1042–1053
Li Y, Upadhyay S, Bhuiyan M, Sarkar FH (1999) Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18:3166–3172
Baxa DM, Yoshimura FK (2003) Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha. Biochem Pharmacol 66:1009–1018
Lamartiniere CA, Moore JB, Brown NM, Thompson R, Hardin MJ, Barnes S (1995) Genistein suppresses mammary cancer in rats. Carcinogenesis 16:2833–2840
Buchler P, Gukovskaya AS, Mouria M, Buchler MC, Buchler MW, Friess H, Pandol SJ, Reber HA, Hines OJ (2003) Prevention of metastatic pancreatic cancer growth in vivo by induction of apoptosis with genistein, a naturally occurring isoflavonoid. Pancreas 26:264–273
Lazarevic B, Boezelijn G, Diep LM, Kvernrod K, Ogren O, Ramberg H, Moen A, Wessel N, Berg RE, Egge-Jacobsen W, Hammarstrom C, Svindland A, Kucuk O, Saatcioglu F, Tasken KA, Karlsen SJ (2011) Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial. Nutr Cancer 63:889–898
Taylor CK, Levy RM, Elliott JC, Burnett BP (2009) The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies. Nutr Rev 67:398–415
Yoshimura FK (2004) Genistein induces apoptosis via mitochondrial damage in acute lymphoblastic leukemia T-cell lines. Cancer Therapy 2:429–440
George J, Banik NL, Ray SK (2010) Genistein induces receptor and mitochondrial pathways and increases apoptosis during BCL-2 knockdown in human malignant neuroblastoma SK-N-DZ cells. J Neurosci Res 88:877–886
Phan V, Walters J, Brownlow B, Elbayoumi T (2013) Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas. J Drug Target 21:1001–1011
Yoon HS, Moon SC, Kim ND, Park BS, Jeong MH, Yoo YH (2000) Genistein induces apoptosis of RPE-J cells by opening mitochondrial PTP. Biochem Biophys Res Commun 276:151–156
Baxa DM, Luo X, Yoshimura FK (2005) Genistein induces apoptosis in T lymphoma cells via mitochondrial damage. Nutr Cancer 51:93–101
Merchant K, Kumi-Diaka J, Rathinavelu A, Esiobu N, Zoeller R, Hartmann J, Johnson M (2011) Molecular basis of the anti-cancer effects of genistein isoflavone in LNCaP prostate cancer cells. Funct Food Health Dis 1:91–105
Stancanelli R, Guardo M, Cannava C, Guglielmo G, Ficarra P, Villari V, Micali N, Mazzaglia A (2010) Amphiphilic cyclodextrins as nanocarriers of genistein: a spectroscopic investigation pointing out the structural properties of the host/drug complex system. J Pharm Sci 99:3141–3149
Cannava C, Crupi V, Ficarra P, Guardo M, Majolino D, Mazzaglia A, Stancanelli R, Venuti V (2010) Physico-chemical characterization of an amphiphilic cyclodextrin/genistein complex. J Pharm Biomed Anal 51:1064–1068
Trapp S, Horobin RW (2005) A predictive model for the selective accumulation of chemicals in tumor cells. Eur Biophys J 34:959–966
Horobin RW, Trapp S, Weissig V (2007) Mitochondriotropics: a review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria. J Control Release 121:125–136
Pham J, Brownlow B, Elbayoumi T (2013) Mitochondria-specific pro-apoptotic activity of genistein lipidic nanocarriers. Mol Pharm 10:3789–3800
Weissig V (2005) Targeted drug delivery to mammalian mitochondria in living cells. Expert Opin Drug Deliv 2:89–102
Whaley WL, Rummel JD, Kastrapeli N (2006) Interactions of genistein and related isoflavones with lipid micelles. Langmuir 22:7175–7184
Kwon SH, Kim SY, Ha KW, Kang MJ, Huh JS, Im TJ, Kim YM, Park YM, Kang KH, Lee S, Chang JY, Lee J, Choi YW (2007) Pharmaceutical evaluation of genistein-loaded pluronic micelles for oral delivery. Arch Pharm Res 30:1138–1143
Weissig V (2011) Mitochondrial delivery of biologically active molecules. Pharm Res 28:2633–2638
Jordan M, Nayel A, Brownlow B, Elbayoumi T (2012) Development and evaluation of tocopherol-rich argan oil-based nanoemulsions as vehicles possessing anticancer activity. J Biomed Nanotechnol 8:944–956
Mu L, Elbayoumi TA, Torchilin VP (2005) Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and d-alpha-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin. Int J Pharm 306:142–149
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Pham, J., Grundmann, O., Elbayoumi, T. (2015). Mitochondriotropic Nanoemulsified Genistein-Loaded Vehicles for Cancer Therapy. In: Weissig, V., Edeas, M. (eds) Mitochondrial Medicine. Methods in Molecular Biology, vol 1265. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2288-8_7
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2288-8_7
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2287-1
Online ISBN: 978-1-4939-2288-8
eBook Packages: Springer Protocols