HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Appropriate modulation of autophagy sensitizes malignant peripheral nerve sheath tumor cells to treatment with imatinib mesylate.

Abstract
Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 μM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.
AuthorsMunehiro Okano, Naoki Sakata, Satoshi Ueda, Tsukasa Takemura
JournalJournal of pediatric hematology/oncology (J Pediatr Hematol Oncol) Vol. 36 Issue 3 Pg. 200-11 (Apr 2014) ISSN: 1536-3678 [Electronic] United States
PMID24136016 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Benzamides
  • Membrane Proteins
  • Piperazines
  • Pyrimidines
  • RNA, Small Interfering
  • 3-methyladenine
  • Imatinib Mesylate
  • Adenine
Topics
  • Adenine (analogs & derivatives, therapeutic use)
  • Antineoplastic Agents (therapeutic use)
  • Apoptosis (drug effects)
  • Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
  • Autophagy (drug effects)
  • Beclin-1
  • Benzamides (therapeutic use)
  • Blotting, Western
  • Cell Survival (drug effects)
  • Flow Cytometry
  • Humans
  • Imatinib Mesylate
  • Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
  • Neurilemmoma (drug therapy, metabolism, pathology)
  • Phagosomes (drug effects)
  • Piperazines (therapeutic use)
  • Pyrimidines (therapeutic use)
  • RNA, Small Interfering (genetics)
  • Signal Transduction
  • Tumor Cells, Cultured

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: