2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy
Por:
S. TERES, V. LLADO, M. HIGUERA, G. BARCELO-COBLIJN, M. MARTIN, M. NOGUERA-SALVA, A. MARCILLA-ETXENIKE, J. GARCIA-VERDUGO, M. SORIANO-NAVARRO, C. SAUS, U. GOMEZ-PINEDO, X. BUSQUETS and P. ESCRIBA
Publicada:
29 may 2012
Resumen:
Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.
Filiaciones:
S. TERES:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
V. LLADO:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
M. HIGUERA:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
G. BARCELO-COBLIJN:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
M. MARTIN:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
M. NOGUERA-SALVA:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
A. MARCILLA-ETXENIKE:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
:
Univ Valencia Estudi Gen, Ctr Invest Biomed Red, Ctr Invest Principe Felipe, Unidad Mixta,Lab Morfol Celular, Valencia 46013, Spain
:
Univ Valencia Estudi Gen, Ctr Invest Biomed Red, Ctr Invest Principe Felipe, Unidad Mixta,Lab Morfol Celular, Valencia 46013, Spain
C. SAUS:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
U. GOMEZ-PINEDO:
Hosp Clin San Carlos, Inst Neurosci, Lab Regenerat Med, Madrid 28040, Spain
X. BUSQUETS:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
P. ESCRIBA:
Univ Balearic Isl, Dept Biol, Inst Univ Invest Ciencies Salut, Palma de Mallorca 07122, Spain
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