This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bedogni, B. Articles by Powell, M. B. Search for Related Content PubMed PubMed Citation Articles by Bedogni, B. Articles by Powell, M. B.

Topical Treatment with Inhibitors of the Phosphatidylinositol 3'-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient Mice

¹ Division of Radiation and Cancer Biology and ² Department of Comparative Medicine, Stanford University, Stanford, California

Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways inhibited the growth of TPras transgenic melanomas in severe combined immunodeficient mice, blocked invasive behavior, and reduced angiogenesis. The inhibitor Ly294002, which is specific for phosphatidylinositol 3'-kinase, effectively reduced melanoma cell growth both in vitro and in vivo. Both Ly294002 and U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, reduced invasion, which correlated with reduction of the metalloproteinase matrix metalloproteinase 2. Tumor angiogenesis was disrupted through inhibition of vascular endothelial growth factor production from the tumor cells and antiangiogenic effects on endothelial cells. Observations with TPras melanoma cells that express dominant negative p85 or kinase-inactive Raf₃₀₁ supported the specificity of the phenomena observed with the chemical inhibitors. These studies demonstrate that topical treatment targeting Ras effectors is efficacious, without systemic toxicities, and may prove to be useful in treating and preventing the progression of cutaneous melanoma.

This article has been cited by other articles:

				N. Jin, T. Jiang, D. M. Rosen, B. D. Nelkin, and D. W. Ball Dual Inhibition of Mitogen-Activated Protein Kinase Kinase and Mammalian Target of Rapamycin in Differentiated and Anaplastic Thyroid Cancer J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 4107 - 4112. [Abstract] [Full Text] [PDF]

				M. A. Tran, R. Gowda, A. Sharma, E.-J. Park, J. Adair, M. Kester, N. B. Smith, and G. P. Robertson Targeting V600EB-Raf and Akt3 Using Nanoliposomal-Small Interfering RNA Inhibits Cutaneous Melanocytic Lesion Development Cancer Res., September 15, 2008; 68(18): 7638 - 7649. [Abstract] [Full Text] [PDF]

				M. A. Tran, C. D. Smith, M. Kester, and G. P. Robertson Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development Clin. Cancer Res., June 1, 2008; 14(11): 3571 - 3581. [Abstract] [Full Text] [PDF]

				Y.-H. Liao, S.-M. Hsu, and P.-H. Huang ARMS Depletion Facilitates UV Irradiation Induced Apoptotic Cell Death in Melanoma Cancer Res., December 15, 2007; 67(24): 11547 - 11556. [Abstract] [Full Text] [PDF]

				Q. Zhou, L.-Z. Liu, B. Fu, X. Hu, X. Shi, J. Fang, and B.-H. Jiang Reactive oxygen species regulate insulin-induced VEGF and HIF-1{alpha} expression through the activation of p70S6K1 in human prostate cancer cells Carcinogenesis, January 1, 2007; 28(1): 28 - 37. [Abstract] [Full Text] [PDF]

				M. Verhaegen, J. A. Bauer, C. Martin de la Vega, G. Wang, K. G. Wolter, J. C. Brenner, Z. Nikolovska-Coleska, A. Bengtson, R. Nair, J. T. Elder, et al. A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase-Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species Cancer Res., December 1, 2006; 66(23): 11348 - 11359. [Abstract] [Full Text] [PDF]

				B. Bedogni, S. M. Welford, A. C. Kwan, J. Ranger-Moore, K. Saboda, and M. B. Powell Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model Mol. Cancer Ther., December 1, 2006; 5(12): 3071 - 3077. [Abstract] [Full Text] [PDF]

				K. Harada, A. B. Truong, T. Cai, and P. A. Khavari The Class II Phosphoinositide 3-Kinase C2{beta} Is Not Essential for Epidermal Differentiation Mol. Cell. Biol., December 15, 2005; 25(24): 11122 - 11130. [Abstract] [Full Text] [PDF]

				N. Ledirac, S. Antherieu, A. D. d'Uby, J.-C. Caron, and R. Rahmani Effects of Organochlorine Insecticides on MAP Kinase Pathways in Human HaCaT Keratinocytes: Key Role of Reactive Oxygen Species Toxicol. Sci., August 1, 2005; 86(2): 444 - 452. [Abstract] [Full Text] [PDF]

				D. L. Dai, M. Martinka, and G. Li Prognostic Significance of Activated Akt Expression in Melanoma: A Clinicopathologic Study of 292 Cases J. Clin. Oncol., March 1, 2005; 23(7): 1473 - 1482. [Abstract] [Full Text] [PDF]