Prevention of UVB-induced skin inflammation, genotoxicity, and photocarcinogenesis in mice by WHI-P131, a dual-function inhibitor of Janus kinase 3 and EGF receptor kinase.
The current study examined the chemopreventive potential of the dual-function JAK3/EGFR tyrosine kinase inhibitor WHI-P131 (CAS 202475-60-3) in photocarcinogenesis of non-melanoma skin cancer (NMSC). Prophylactic WHI-P131 exhibited significant anti-inflammatory activity in the SKH-1 mouse model of sunburn and afforded significant protection against the inflammatory skin damage that results from UVB exposure. UVB exposure (400 mJ/cm2) increased the mutation rate of the transgene target in UVB-exposed skin of BigBlue mice by a factor of 3.7 from 8.6 x 10(-5) to 31.7 x 10(-5) but this genotoxicity was almost completely prevented by topically administered prophylactic WHI-Pl31 (1.5 mg/cm2). Chronic and repetitive exposure of vehicle-treated SKH-1 mice to 35 mJ/cm2 UVB, three times per week for 20 weeks resulted in appearance of a spectrum of lesions from actinic keratoses and squamous cell carcinoma (SCC) in situ to invasive SCC. Both the number and size of the skin lesions progressively increased over time. Notably, topical administration of WHI-P131 (1.0 mg/cm2) over the UVB target skin area on the dorsal surface 15 min before each UVB exposure significantly suppressed the photocarcinogenesis as documented by a 4-week delay in the onset of visible skin lesions, decreased total lesion volume per mouse (1.9 +/- 0.5 mm3 vs. 2.5 +/- 0.5 mm3/lesion at 20 weeks), and decreased number (1.6 +/- 0.4/mouse vs. 4.2 +/- 1.6/mouse at 20 weeks, P < 0.05) as well as smaller size of lesions and consequently a smaller total lesion volume ("skin cancer burden") (10.6 +/- 4.3 mm3 vs. 3.2 +/- 0.9 mm3 at 20 weeks, P < 0.05). These experimental findings provide unprecedented evidence that WHI-P131 may be useful as a chemopreventive agent against NMSC.
Uckun
Fatih M
FM
Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA, USA. fmuckun@chla.usc.edu
Dibirdik
Ilker
I
Qazi
Sanjive
S
D000287:Administration, Topical; D000818:Animals; D016587:Antimutagenic Agents; D003872:Dermatitis / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays
D016587:Antimutagenic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C116180:WHI P131; D066246:ErbB Receptors; D053616:Janus Kinase 3