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

Fatih M Uckun; Ilker Dibirdik; Sanjive Qazi

doi:10.1055/s-0031-1296276

Arzneimittelforschung, Inhaltsverzeichnis

Arzneimittelforschung 2010; 60(4): 218-225
DOI: 10.1055/s-0031-1296276

Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics

Editio Cantor Verlag Aulendorf (Germany)

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

Fatih M Uckun

¹Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA, USA

²Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

³Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

,

Ilker Dibirdik

³Molecular Oncology and Drug Discovery Program, Parker Hughes Institute, St. Paul, MN, USA

,

Sanjive Qazi

⁴Bioinformatics Program, Gustavus Adolphus College, St. Peter, MN, USA

› Institutsangaben

Abstract

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 _× 10⁻⁵ to 31.7 _× 10⁻⁵ but this genotoxicity was almost completely prevented by topically administered prophylactic WHI-P131 (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.

Key words

CAS 202475-60-3 - JAK3 tyrosine kinase inhibitor - Non-melanoma skin cancer, chemoprevention - Photocarcinogenesis - WHI-P131

Volltext

Referenzen

References
1 Marks R. An overview of skin cancers: incidence and causation. Cancer. 1995; 75: 607-12
2 Miller DL, Weinstock MA. Non-melanoma skin cancer in the United States: Incidence. J Am Acad Dermatol. 1994; 30: 774-776
3 Leffell DJ, Carucci JA. Management of skin cancer. In: De-Vita Jr VT, Hellman S, Rosenberg SA. editors Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001: 1976-98
4 Uckun FM, Vassilev A, Dibirdik I, Tibbles H. Targeting JAK3 tyrosine kinase-linked signal transduction pathways with rationally designed inhibitors. Anticancer Agents Med Chem. 2007; 7: 612-23
5 Uckun FM, Tibbles H, Ozer Z, Qazi S, Vassilev A. Anti-inflammatory activity profile of JANEX-1 in preclinical animal models. Bioorg Med Chem. 2008; 16: 1287-98
6 Malaviya R, Zhu D, Dibirdik I, Uckun FM. Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis. J Biol Chem. 1999; 274: 27028-38
7 Goodman PA, Niehoff LB, Uckun FM. Role of tyrosine kinases in induction of the c-jun proto-oncogene in irradiated B-lineage lymphoid cells. J Biol Chem. 1998; 273: 17742-8
8 Liu YP, Tan YN, Wang ZL, Zeng L, Lu ZX, Li LL et al Phosphorylation and nuclear translocation of STAT3 regulated by the Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. Int J Mol Med. 2008; 21: 153-62
9 Scharfe N, Dadi HK, Roifman CM. JAK3 protein tyrosine kinase mediates interleukin-7 induced activation of phos-phatidylinositol-3 kinase. Blood. 1995; 86: 2077-85
10 Suiqing C, Min Z, Lirong C. Overexpression of phosphory-lated STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma. J Dermatol. 2005; 32: 354-60
11 Welss T, Papoutsaki M, Michel G, Reifenberger J, Chimenti S, Ruzicka T et al Molecular basis of basal cell carcinoma: analysis of differential gene expression by differential display PCR and expression array. Int J Cancer. 2003; 10: 66-72
12 Serewko MM, Popa C, Dahler AL, Smith L, Strutton GM, Coman W et al Alterations in gene expression and activity during squamous cell carcinoma development. Cancer Res. 2002; 62: 3759-65
13 Kim AL, Athar M, Bickers DR, Gautier J. Stage-specific alterations of cyclin expression during UVB-induced murine skin tumor development. Photochem Photobiol. 2002; 75: 58-67
14 Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P et al Reduced skin tumor development in cyclin Dl-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev. 1998; 12: 2469-74
15 Sauter ER, Nesbit M, Litwin S, Klein-Szanto AJ, Cheffetz S, Herlyn M. Antisense cyclin Dl induces apoptosis and tumor shrinkage in human squamous carcinomas. Cancer Res. 1999; 59: 4876-81
16 Hsu TC, Young MR, Cmarik J, Colburn NH. Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-de-pendent transcriptional events in carcinogenesis. Free Radic Biol Med. 2000; 28: 1338-48
17 Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W et al Cyclin Dl is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 2006; 66: 2544-52
18 Sudbeck EA, Liu X, Narla RK, Mahajan S, Ghosh S, Mao C et al Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin Cancer Res. 1999; 5: 1569-82
19 Cetkovic-Cvrlje M, Roers BA, Waurzyniak B, Liu XP, Uckun FM. Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibiloity barrier in mice. Blood. 2001; 98: 1607-13
20 Cetkovic-Cvrlje M, Dragt AL, Vassilev A, Liu XP, Uckun FM. Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. Clin Immunol. 2003; 106: 213-25
21 Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatika-kis I et al Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines. Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005; 167: 969-80
22 Amin HM, Medeiros LJ, Ma Y, Feretzaki M, Das P, Leventaki V et al Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Oncogene. 2003; 22: 5399-407
23 Hu W, Zhang C, Zhang P, Wei D, Zhao Z, Cai M. Inhibition of constitutively activated JAK3 and induction of apoptosis in NALM-6 cell line. Hua Xi Yi Ke Da Xue Bao. 2002; 33: 25-7
24 Uckun FM, Erbeck D, Qazi S, Venkatachalam T, Tibbles HE, Vassilev A. Effect of targeting Janus Kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli (min) mouse model of familial adenomatous polyposis. Nutr Cancer. Forthcoming. 2010;
25 Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP et al Defective lymphoid development in mice lacking Jak3. Science. 1995; 270: 800-2
26 Jakubczak JL, Merlino G, French JE, Muller WJ, Paul B, Adhya S et al Analysis of genetic instability during mammary tumor progression using a novel selection-based assay for in vivo mutations in a bacteriophage lambda transgene target. Proc Natl Acad Sci USA. 1996; 93: 9073-8
27 Morris RJ, Tacker KC, Baldwin JK, Fischer SM, Slaga TJ. A new medium for primary cultures of adult murine epidermal cells: application to experimental carcinogenesis. Cancer Lett. 1987; 34: 297-304
28 Kligman LH, Akin FJ, Kligman AM. Prevention of ultraviolet damage to the dermis of hairless mice by sunscreens. J Invest Dermatol. 1982; 78: 181-9
29 Learn DB, Beasley DG, Giddens LD, Beard J, Stanfield JW, Roberts LK. Minimum doses of ultraviolet radiation required to induce murine skin edema and immunosuppression are different and depend on the ultraviolet emission spectrum of the source. Photochem Photobiol. 1995; 62: 1066-75
30 Uckun FM, Ek O, Liu XP, Chen CL. In vivo toxicity and pharmacokinetic features of the janus kinase 3 inhibitor WHI-P131[4-(4’hydroxyphenyl)-amino-6,7-dimethoxyqui-nazoline. Clin Cancer Res. 1999; 5: 2954-62
31 Narla RK, Liu X, Klis D, Uckun FM. Inhibition of human glioblastoma cell adhesion and invasion by 4-(4’-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3’-bromo-4’-hydroxylphenyl)-amino-6,7-dimethoxyqui-nazoline (WHI-P154). Clin Cancer Res. 1998; 4: 2463-71
32 Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004; 4: 71-8
33 Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z et al Inflammatory mast cells up- regulateangiogenesisduringsquamousepithelial carcinogenesis. Genes Dev. 1999; 13: 1382-97
34 Ardestani SK, Inserra P, Solkoff D, Watson RR. The role of cytokines and chemokines on tumor progression: a review. Cancer Detect Prev. 1999; 23: 215-25
35 Fitzpatrick FA. Inflammation, carcinogenesis and cancer. Int Immunopharmacol. 2001; 1: 1651-67
36 Li WQ, Dehnade F, Zafarullah M. Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metallo-proteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J Immunol. 2001; 166: 3491-8
37 Kim S, Kim Y, Lee Y, Chung JH. Ceramide accelerates ultra-violet-induced MMP-1 expression through JAK/STAT pathway in cultured human dermal fibroblasts. J Lipid Res. 2008; 49: 2571-81
38 Kang-Rotondo CH, Miller CC, Morrison AR, Pentland AP. Enhanced keratinocyte prostaglandin synthesis after UV injury is due to increased phospholipase activity. Am J Physiol. 1993; 264: C396-401
39 An KP, Athar M, Tang X, Katiyar SK, Russo J, Beech J et al Cyclooxygenase-2 expression in murine and human non-melanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol. 2002; 76: 73-80
40 Rundhaug JE, Fischer SM. Cyclooxygenase 2 plays a critical role in UV induced skin carcinogenesis. Photochem Photobiol. 2008; 84: 322-9
41 El-Abaseri TB, Putta S, Hansen LA. Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis. 2006; 27: 225-31
42 Cooper SJ, Bowden GT. Ultraviolet B regulation of transcription factor families: roles of nuclear factor kappa B (NFkB) and activator protein-1 (AP-1) in UVB-induced skin carcinogenesis. Curr Cancer Drug Targets. 2007; 7: 325-34