Combination of KIT gene silencing and tocopherol succinate may offer improved therapeutic approaches for human mastocytosis.
Gain-of-function mutations of kit tyrosine kinase receptor are associated with mastocytosis. Two subclones of the HMC1 mast leukaemia cell line were used; both express an identical KIT allele-specific regulatory type mutation (V560G), but differ in that one also expresses an enzymatic site type mutation (D816V) that confers on them resistance to imatinib mesylate tyrosine kinase inhibitor. In both cell lines, proliferation was suppressed and apoptosis induced by the combination of KIT gene silencing and alpha-tocopherol succinate (alpha-TOS), a derivate of alpha-tocopherol, also known as vitamin E. Furthermore, HMC1 cells with decreased kit levels by KIT silencing, failed to form tumours when xenotransplanted into immunocompromised mice and the animals were treated systemically with alpha-TOS. Targeting kit in the presence of alpha-TOS represents a new approach against proliferation of human mast leukaemia cell lines.
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain.
Irene
I
Ruano
Ricardo
R
Gargini
Marta
M
Izquierdo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003131:Combined Modality Therapy; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008415:Mastocytosis / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D024502:alpha-Tocopherol / Q000627:therapeutic use*
D019009:Proto-Oncogene Proteins c-kit; D024502:alpha-Tocopherol