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

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.

• Authors: Jun Ohishi, Mikiko Aoki, Kazuki Nabeshima, Junji Suzumiya, Tamotsu Takeuchi, Akira Ogose, Michiyuki Hakozaki, Yuichi Yamashita, Hiroshi Iwasaki
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 224 (May 04 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23642185 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• RNA, Messenger
• Imatinib Mesylate
• Receptor, Platelet-Derived Growth Factor alpha
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Benzamides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Imatinib Mesylate
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Neoplastic Stem Cells (drug effects)
• Nerve Sheath Neoplasms (drug therapy, genetics)
• Phosphorylation (drug effects)
• Piperazines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, genetics, metabolism)