TY - JOUR
T1 - Ras inhibition by FTS attenuates brain tumor growth in mice directly and by enhancing reactivity of cytotoxic lymphocytes
AU - Aizman, Elizabeta
AU - Mor, Adi
AU - Levy, Ayelet
AU - George, Jacob
AU - Kloog, Yoel
PY - 2012/2
Y1 - 2012/2
N2 - One of the concerns in targeted drug therapy is that the inhibition of receptors and signaling molecules in tumor cells may also affect similar components in the tumor microenvironment or in the immune system, with undefined consequences for inhibition of tumor growth. Thus, in addition to its antitumor activity in mice and humans, the Ras inhibitor salirasib (S-farnesylthiosalicylic acid, FTS) also exhibits anti-inflammatory activity. Here we show three antitumor effects of FTS in immune-competent mice with subcutaneous or intracranial tumors. First, FTS exhibited antitumor activity in immune-competent, intracranial tumor-bearing mice and increased their survival relative to tumor-bearing immune-compromised mice. Second, FTS induced an increase in regulatory T cells in mouse splenocytes, but the inhibitory effects of FTS on tumor growth were not affected by these Foxp3+ T lymphocytes. Third, FTS increased antitumor T-cell reactivity by downregulating Foxp3. This caused TGF-β-dependent sensitization of the tumor to the immune system.
AB - One of the concerns in targeted drug therapy is that the inhibition of receptors and signaling molecules in tumor cells may also affect similar components in the tumor microenvironment or in the immune system, with undefined consequences for inhibition of tumor growth. Thus, in addition to its antitumor activity in mice and humans, the Ras inhibitor salirasib (S-farnesylthiosalicylic acid, FTS) also exhibits anti-inflammatory activity. Here we show three antitumor effects of FTS in immune-competent mice with subcutaneous or intracranial tumors. First, FTS exhibited antitumor activity in immune-competent, intracranial tumor-bearing mice and increased their survival relative to tumor-bearing immune-compromised mice. Second, FTS induced an increase in regulatory T cells in mouse splenocytes, but the inhibitory effects of FTS on tumor growth were not affected by these Foxp3+ T lymphocytes. Third, FTS increased antitumor T-cell reactivity by downregulating Foxp3. This caused TGF-β-dependent sensitization of the tumor to the immune system.
KW - CTL
KW - FTS
KW - Glioblastoma
KW - Ras
KW - Salirasib
UR - http://www.scopus.com/inward/record.url?scp=84863795404&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.420
DO - 10.18632/oncotarget.420
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AN - SCOPUS:84863795404
SN - 1949-2553
VL - 3
SP - 144
EP - 157
JO - Oncotarget
JF - Oncotarget
IS - 2
ER -