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. 2013 May 4:13:224.
doi: 10.1186/1471-2407-13-224.

Imatinib mesylate inhibits cell growth of malignant peripheral nerve sheath tumors in vitro and in vivo through suppression of PDGFR-β

Jun Ohishi  1 , Mikiko Aoki, Kazuki Nabeshima, Junji Suzumiya, Tamotsu Takeuchi, Akira Ogose, Michiyuki Hakozaki, Yuichi Yamashita, Hiroshi Iwasaki
Affiliations

Imatinib mesylate inhibits cell growth of malignant peripheral nerve sheath tumors in vitro and in vivo through suppression of PDGFR-β

Jun Ohishi et al. BMC Cancer. .

Abstract

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed.

Methods: The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model.

Results: The results showed expression of platelet-derived growth factor receptor-β and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 μM) in three of six cell lines. Knockdown of PDGFR-β by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis.

Conclusions: The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo.

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Figures

Figure 1
Figure 1
Expression of PDGFR proteins and mRNAs of in six MPNST cell lines analyzed by western blotting (A) and real-time RT-PCR (B). The mRNA expression levels in each cell line were compared with the levels in FU-SFT8611 cells. PDGFR-β protein and mRNA were expressed in all MPNST cell lines. The expression of PDGFR-α protein was observed in all but HS-Sch-2 cells. The PDGFR-α mRNA level in NMS-2 and NMS-2PC cells was higher than in the other four cell lines. Data in (B) is the mean ± SEM (n = 3). Similar results were obtained in three independent experiments. *P < 0.01, compared with the level in FU-SFT8611 cells (by Student’s t-test).
Figure 2
Figure 2
Effects of PDGF-BB and imatinib mesylate on phosphorylation of PDGFRs. PDGFR-β of all six MPNST cell lines was phosphorylated in response to 25 ng/ml of PDGF-BB for 30 min. PDGF-BB stimulation did not induce any phosphorylation of PDGFR-α in all cell lines. Pretreatment with 10 μM imatinib mesylate almost completely suppressed PDGF-BB-induced PDGFR-β phosphorylation in all cell lines.
Figure 3
Figure 3
Effects of imatinib mesylate on the proliferation of six MPNST cell lines. MPNST cells were incubated for 5 days with imatinib mesylate at the indicated concentrations in media containing 2% FCS. One to five μM of imatinib mesylate had significant inhibitory effects at day 5 in three cell lines, FU-SFT9817, HS-Sch-2, and FMS-1 cells. Data are the means ± SEM (n = 4). *P < 0.01, compared with the control group without imatinib mesylate (by Student’s t-test).
Figure 4
Figure 4
Effects of siRNA-mediated inhibition of PDGFR-β expression on the growth of 3 MPNST cell lines. After 72 h transfection with 0.01, 0.02 and 0.05 pmol/μl siRNA, specific PDGFR-β knockdown was induced in all three cell lines. In the presence of 0.02 pmol/μl siRNA for PDGFR-β, cell proliferation was significantly inhibited compared with the control, in two MPNST cell lines, HS-Sch-2 (A) and FMS-1 (B), but not NMS-2PC (C). Data are the means ± SEM (n = 5). Similar results were obtained in at least two independent experiments. *P < 0.01 (by Student’s t-test).
Figure 5
Figure 5
Soft agar colony formation assay. Anchorage-independent growth in soft agar was examined under different concentrations of imatinib mesylate, and numbers of colonies were counted at day 7. (A) Numbers of anchorage-independent colonies of HS-Sch-2 cells growing in the soft agar were scored using phase contrast microscopy. (B) Imatinib mesylate at 5 μM significantly decreased the number of colonies of HS-Sch-2 and FMS-1 cells, but had no effect on NMS-2PC cells. Data are the means ± SEM (n = 6). *P < 0.01, compared with the control group without imatinib mesylate (by Student’s t-test).
Figure 6
Figure 6
Effects of oral treatment with imatinib mesylate on tumor growth in mice of the xenograft model. One group of mice was treated with 100 mg/kg/day imatinib mesylate (■; treatment group) while the other was treated with water (○; control group). (A, left) Xenografts were established by injection of HS-Sch-2 cells in female NOD/SCID mice. The tumor volume was significantly smaller in the treatment group than the control (■; n = 5, ○; n = 6, *P < 0.01, by Student’s t-test) on day 28. (B, left) Imatinib mesylate significantly reduced the growth of FMS-1 xenografts compared with the control groups (■; n = 7, ○; n = 6, **P < 0.05, by Student’s t-test). (C, left) Imatinib mesylate did not affect the growth of NMS-2PC xenografts (■; n = 4, ○; n = 4). Representative picture of animals are shown at right for each experiment.
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