| Reference | 1. Oncol Rep. 2011 Jun;25(6):1565-71. doi: 10.3892/or.2011.1233. Epub 2011 Mar 23.
<br>
The insulin-like growth factor-I receptor kinase inhibitor NVP-ADW742 sensitizes
medulloblastoma to the effects of chemotherapy.
<br>
Zhou H(1), Rao J, Lin J, Yin B, Sheng H, Lin F, Zhang N, Yang L.
<br>
Author information: <br>
(1)Department of Neurosurgery, The 2nd Affiliated Hospital of Wenzhou Medical
College, Wenzhou 325000, PR China.
<br>
Medulloblastoma is the most common malignant tumor of the central nervous system
in children. The insulin-like growth factor-I receptor (IGF-IR) is an important
growth factor for medulloblastoma. The novel IGF-I receptor (IGF-IR) kinase
inhibitor NVP-ADW742 has in vitro activity against tumors. Daoy cells were
treated with NVP-ADW742 combined with temozolomide, which is commonly used in the
chemotherapy of medulloblastoma. The effects on proliferation were assayed by
CCK-8 assay. Cell cycle status and apoptosis were assayed by FACS analysis. The
IGF-IR signaling pathway was analyzed by RT2 Profiler™ PCR arrays and Western
blotting. NVP-ADW742 inhibited IGF-IR-mediated proliferation with an IC50 of
11.12 μmol/l. The PCR array data suggested that 14 genes were down-regulated at
the mRNA level after NVP-ADW742 treatment. Western blot analysis suggested that
NVP-ADW742 induced early suppression of Akt, P38 and GSK-3β phosphorylation, as
well as a decrease in the intracellular levels of PI3K, Akt, P38, GSK-3β and
Bcl-2. Combined with NVP-ADW742 (2 μmol/l), IC50 of Daoy to temozolomide was
decreased from 452.12 to 256.81 μmol/l. Cell apoptosis was enhanced from
16.18±2.47% to 23.20 ± 2.80%. G phase arrest was also found in both the
temozolomide alone group and the temozolomide combined with NVP-ADW742 group.
NVP-ADW742 inhibited the activation of PI3K, Akt, P38 and GSK-3β caused by
temozolomide. NVP-ADW742 enhanced the chemosensitivity of Daoy to temozolomide in
vitro, as a potent anti-tumor agent highly selective against IGF-IR.
<br>
2. Oncol Res. 2010;19(1):35-43.
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The insulin-like growth factor-1 receptor kinase inhibitor, NVP-ADW742,
suppresses survival and resistance to chemotherapy in acute myeloid leukemia
cells.
<br>
He Y(1), Zhang J, Zheng J, Du W, Xiao H, Liu W, Li X, Chen X, Yang L, Huang S.
<br>
Author information: <br>
(1)Center for Stem Cell Research and Application, Institute of Hematology, Union
Hospital of Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China.
<br>
Deregulation of insulin-like growth factor-1 receptor (IGF-1R) is closely
associated with malignant transformation and tumor cell survival in various
cancers. We found that IGF-1R expression level in leukemia cells positively
correlated with the percentage of blast in bone marrow from de novo acute myeloid
leukemia (AML) patients. Moreover, we showed that NVP-ADW742, a novel small
weight molecular inhibitor of IGF-IR, could induce apoptosis in both HL-60 cell
line and primary AML blasts. However, no significant alteration of cell cycle was
observed in HL-60 cells. Further studies revealed that NVP-ADW742 induced Akt
dephosphorylation, which might subsequently induce p38 phosphorylation and
decrease antiapoptotic protein Bcl-2 expression in HL-60 cells. Finally, we
demonstrated that NVP-ADW742 could synergize with Ara-C to induce the kill in a
subset of drug-resistant AML specimens. We suggested that IGF-lR targeting might
be therapeutically beneficial for some AML patients.
<br>
3. Clin Cancer Res. 2005 Feb 15;11(4):1563-71.
<br>
The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742,
sensitizes small cell lung cancer cell lines to the effects of chemotherapy.
<br>
Warshamana-Greene GS(1), Litz J, Buchdunger E, García-Echeverría C, Hofmann F,
Krystal GW.
<br>
Author information: <br>
(1)Department of Medicine, Virginia Commonwealth University and McGuire Veterans
Affairs Medical Center, Richmond, VA 23249, USA.
<br>
PURPOSE: Insulin-like growth factor-I (IGF-I) is a potent growth factor for small
cell lung cancer (SCLC) in both the autocrine and endocrine context. It also
inhibits chemotherapy-induced apoptosis through activation of the
phosphatidylinositol 3-kinase (PI3K)-Akt pathway and we have previously shown
that inhibition of this signaling pathway enhances sensitivity of SCLC cell lines
to chemotherapy. The purpose of this study was to determine whether the novel
IGF-I receptor (IGF-IR) kinase inhibitor, NVP-ADW742, sensitizes SCLC cell lines
to etoposide and carboplatin, which are commonly used in the treatment of SCLC.
EXPERIMENTAL DESIGN: Cell growth in the presence of various combinations of
NVP-ADW742, imatinib (STI571; Gleevec/Glivec), and chemotherapeutic agents was
monitored using a 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide
(MTT) assay and analyzed using the Chou-Talalay multiple-drug-effect equation.
Induction of apoptosis was assessed using terminal deoxynucleotide
transferase-mediated dUTP nick end labeling (TUNEL) and Western blot analysis of
procaspase 3 and poly(ADP-ribose)polymerase cleavage. IGF-I-induced vascular
endothelial cell growth factor expression was monitored by Northern blot and
ELISA.<br>
RESULTS: NVP-ADW742 synergistically enhanced sensitivity of multiple SCLC cell
lines to etoposide and carboplatin. Maximal enhancement occurred at
concentrations of NVP-ADW742 that eliminated basal PI3K-Akt activity in
individual cell lines. In the WBA cell line, in which the c-Kit receptor tyrosine
kinase is partly responsible for basal PI3K-Akt activity, the combination of
NVP-ADW742 and imatinib was superior to NVP-ADW742 alone in sensitizing the cells
to etoposide. Enhancement of the sensitivity of SCLC cell lines to etoposide, as
determined by MTT assay, correlated closely with sensitization to the induction
of apoptosis as measured by TUNEL and caspase activation assays. Treatment with
NVP-ADW742 also eliminated IGF-I-mediated expression of vascular endothelial cell
growth factor, suggesting that in addition to enhancing sensitivity of SCLC to
chemotherapy, this kinase inhibitor could potentially inhibit angiogenesis in
vivo.<br>
CONCLUSIONS: Inhibition of IGF-IR signaling synergistically enhances the
sensitivity of SCLC to etoposide and carboplatin. This enhancement in sensitivity
to chemotherapy tightly correlates with inhibition of PI3K-Akt activation. Future
SCLC clinical trials incorporating IGF-IR inhibitors alone or in combination with
other kinase inhibitors should include assessment of PI3K-Akt activity as a
pharmacodynamic end-point.<br>
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