Abstract
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 Δp85 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2552-2560 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 64 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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. / Bedogni, Barbara; O'Neill, Melony S.; Welford, Scott; Bouley, Donna M.; Giaccia, Amato J.; Denko, Nicholas C.; Powell, Marianne Broome.
In: Cancer Research, Vol. 64, No. 7, 01.04.2004, p. 2552-2560.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Bedogni, Barbara
AU - O'Neill, Melony S.
AU - Welford, Scott
AU - Bouley, Donna M.
AU - Giaccia, Amato J.
AU - Denko, Nicholas C.
AU - Powell, Marianne Broome
PY - 2004/4/1
Y1 - 2004/4/1
N2 - 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 Δp85 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.
AB - 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 Δp85 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=1942442169&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-03-3327
DO - 10.1158/0008-5472.CAN-03-3327
M3 - Article
C2 - 15059911
AN - SCOPUS:1942442169
VL - 64
SP - 2552
EP - 2560
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 7
ER -