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Istituto di scienza dell'alimentazione

Torna all'elenco Contributi in atti di convegno anno 2008

Contributo in atti di convegno

Tipo: Poster

Titolo: Valproic acid restores K562 leukemia cell responsiveness to TRAIL/Apo2L mediated apoptosis

Anno di pubblicazione: 2008

Formato: Cartaceo

Autori: Giuseppe Iacomino

Affiliazioni autori: ISA-CNR

Autori CNR:

  • GIUSEPPE IACOMINO

Lingua: inglese

Abstract: Targeting death receptors to trigger apoptosis in cancer cells appears ideal in cancer therapy.The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is of great interest since it has been shown to predominantly kill cancer cells with minor effects on normal counterparts, thus representing a promising anticancer agent (1). However, resistance towards TRAIL/Apo2L treatment has also been described. To overcome this obstacle, co-administration of TRAIL/Apo2L plus several compounds, including histone deacetylase inhibitors (HDACi), have been attempted as an approach to restore sensitivity to TRAIL-induced apoptosis (2). In recent years, the clinical application of HDACi has been largely explored since their ability to modulate gene transcription, block cell division cycle, inhibit cell proliferation, induce cellular differentiation and apoptosis. Aim of this study was to evaluate the aptitude of valproic acid (VPA), a well-known HDACi, to sensitise K562 cell line to TRAIL/Apo2L mediated apoptosis. We chose the human K562 leukaemia cell line, since it exhibited a relatively low response to TRAIL/Apo2L. Moreover, we selected VPA, since it is currently used in clinical practice and its pharmacokinetic, pharmacodynamic and bioavailability are known. Consistently with previous papers, deep alterations in anti-apoptotic and pro-apoptotic signals were found upon VPA treatment (3). Concurrent events, involving K562 cell differentiation, surface expression of the cell death receptors, the DISC composition, and the mitochondria status, seem to be all responsible for the observed synergism in inducing apoptosis following VPA and TRAIL/Apo2L combinatorial administration. When associated to TRAIL/Apo2L, VPA increased cell death and caspase-3 activity by 4-fold compared to the treatment with TRAIL/Apo2L alone. VPA sensitized K562 cells to TRAIL/Apo2L-mediated apoptosis by increasing the expression of DR4 and DR5 by 3- and 14-fold respectively. In addition, VPA per se, in the absence of TRAIL/Apo2L, decreased the expression of anti-apoptotic factors, such as c-FLPs, associated to DISC, and Bcl-2/Bcl-XL, associated to mitochondria, acting on both extrinsic and intrinsic apoptotic pathways. In summary, our results demonstrated the ability of VPA to sensitize TRAIL/Apo2L-resistant cells to apoptosis, thus providing an attracting weapon for the treatment of leukemias and other proliferative malignancies. References: 1 Falschlehner C, Emmerich CH, Gerlach B and Walczak H: TRAIL signalling: Decisions between life and death. Int J Biochem Cell Biol 39(7-8): 1462-1475, 2007. 2 Fulda S and Debatin KM: HDAC inhibitors: double edge sword for TRAIL cancer therapy? Cancer Biol Ther 4(10): 1113-1115, 2005. 3 Iacomino G, Medici MC, Russo GL: Valproic acid sensitizes K562 erythroleukemia cells to TRAIL/Apo2L-induced apoptosis. Anticancer Res. 28(2A):855-64, 2008

Parole chiave:

  • Apoptosis
  • Cell Stress
  • TRAIL
  • Valproic acid

Congresso nome: Cell stress and apoptosis

Congresso luogo: Salerno

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