title: Enhanced Percutaneous Delivery of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) Methane for Skin Cancer Chemoprevention.
abstract: Skin cancer has high incidence in the United States and is mainly caused by ultraviolet B (UVB) radiation. In this study, we demonstrated the role of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (DIM-D) in the prevention of skin photocarcinogenesis using an in vivo UVB-induced skin cancer model. We also evaluated the efficiency of oleic acid-modified nanostructured lipid carriers to deliver DIM-D across the skin barrier into the epidermis for chemopreventive activity. Nanocarriers were 203.00 ± 21.21 nm in diameter with polydispersity, zeta potential and entrapment efficiency of 0.33 ± 0.01, 37.17 ± 0.90 mV and 93.64 ± 0.65%, respectively. Oleic acid-modified nanocarriers were incorporated into Hydroxypropyl methylcellulose to form DIM-D-Nanogel (DIM-D-N). DIM-D-N pretreatment prior to UVB exposure delayed tumor initiation and reduced tumor multiplicity (p < 0.05) at the end of the study compared to Epigallocatechin gallate (EGCG) gel pretreatment. DIM-D-N pretreatment decreased UVB-induced damage to skin lipids and proteins (p < 0.05), respectively by 7.63 and 2.56-fold less than EGCG gel pretreatment and by 17.86 and 11.92-fold less than UVB-only treatment. Histology showed rete-ridge extension, epidermal thickening and hyperkeratosis for UVB-only treatment and EGCG gel pretreatment; DIM-D-N pretreatment showed similar features as the negative control. Western blot analysis showed increased Nurr1 expression (p < 0.05) for DIM-D-N pretreated group compared to EGCG gel (4.68-fold). DIM-D-N pretreatment reduced BCI-2 expression (p < 0.05) but increased Bax and cPARP. Knock down studies with Nurr1 siRNA reduced the expressions of Nurr1 and cPARP by 8.18 and 1.45-fold, respectively (p < 0.05). Our results suggest the role of DIM-D in skin cancer chemoprevention mediated by possible molecular therapeutic targets such as Nurr1.
authors: Cedar H A
authors: CH
authors: Boakye
authors: Punit P
authors: PP
authors: Shah
authors: Ravi
authors: R
authors: Doddapaneni
authors: Apurva R
authors: AR
authors: Patel
authors: Stephen
authors: S
authors: Safe
authors: Mandip
authors: M
authors: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D004058:Diffusion; D004357:Drug Synergism; D005260:Female; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D010316:Particle Size; D012869:Skin Absorption; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C512018:1,1-bis(3'-indolyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; D053769:Nanocapsules