Valproic acid sensitizes K562 erythroleukemia cells to TRAIL/Apo2L-induced apoptosis

Abstract

Background: Selectively 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 without toxic effects on normal counterparts, thus representing a promising anticancer agent. 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), has been attempted as a strategy to restore cancer cell sensitivity to TRAIL-induced apoptosis. In recent years, the clinical application of HDACi has been largely explored for their ability to modulate gene transcription, block cell division cycle, inhibit cell proliferation, induce cellular differentiation and apoptosis.

Materials and methods: The ability of valproic acid (VPA), a well-known HDACi, to sensitise the K562 cell line, derived from a human leukemia, to TRAIL/Apo2L-mediated apoptosis was evaluated. VPA was selected since it is currently used in clinical practice and its pharmacokinetic, pharmacodynamic and bioavailability are known.

Results: When applied with 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, reduced the expression of antiapoptotic factors, such as c-FLPs, associated with DISC, and Bcl-2/Bcl-X(L), associated with mitochondria, acting on both extrinsic and intrinsic apoptotic pathways.

Conclusion: Our results demonstrated the ability of VPA to sensitize TRAIL/Apo2L-resistant cells to apoptosis, thus providing an attractive approach for the treatment of leukemias and other proliferative malignancies.