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Radiation Oncology (London, England) Dec 2009Glioblastoma multiforme (GBM) is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has...
PURPOSE
Glioblastoma multiforme (GBM) is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy.
MATERIALS AND METHODS
Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds) DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK)-3beta, and other proteins. A murine xenograft tumor flank model was used for in vivo radiosensitization studies.
RESULTS
MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3beta. In vivo, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time.
CONCLUSIONS
GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both in vitro and in vivo, and may help to improve outcomes for patients with GBM.
Topics: Animals; Apoptosis; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Comet Assay; DNA Breaks, Double-Stranded; Glioblastoma; Humans; Mice; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrimidines; RNA, Small Interfering; Radiation Tolerance; Thiourea; Xenograft Model Antitumor Assays
PubMed: 20028557
DOI: 10.1186/1748-717X-4-69 -
BMC Cancer May 2009Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The...
BACKGROUND
Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo.
METHODS
The efficacy of MP470 or MP470 plus Erlotinib was evaluated in vitro using three prostate cancer cell lines by MTS and apoptosis assays. The molecular mechanism study was carried out by phosphorylation antibody array, immunoblotting and immunohistochemistry. A LNCaP mouse xenograft model was also used to determine the tumor growth inhibition by MP470, Erlotinib or the combination treatments.
RESULTS
MP470 exhibits low microM IC50 in prostate cancer cell lines. Additive effects on both cytotoxicity and induction of apoptosis were observed when LNCaP were treated with MP470 in combination with Erlotinib. This combination treatment completely inhibited phosphorylation of the HER family members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity even after androgen depletion. Furthermore, in a LNCaP mouse xenograft model, the MP470-Erlotinib combination produced 30-65% dose-dependent tumor growth inhibition (TGI).
CONCLUSION
We propose that MP470-Erlotinib targets the HER family/PI3K/Akt pathway and may represent a novel therapeutic strategy for prostate cancer.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Therapy, Combination; ErbB Receptors; Erlotinib Hydrochloride; Humans; Male; Mice; Mice, SCID; Multigene Family; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperazines; Prostatic Neoplasms; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Thiourea
PubMed: 19432987
DOI: 10.1186/1471-2407-9-142