Valproic acid overcomes hypoxia-induced resistance to apoptosis

Abstract

Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O2) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O2), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment.

Activation of AMP-Activated Protein Kinase α and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells

“…The hypoxic cells are considered more aggressive and resistant to various therapies including radiation or chemotherapy [19, 20]. Therefore, the cytotoxic effects of CB-PIC were evaluated in human SW 620 colorectal cancer cells under hypoxia or normoxia.…”

Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income country: Metro-Mali-02

“…Valproic acid may have a role in these anti-tumor effect since it has been showed to have activity in neuroblastoma, [11,12] osteosarcoma [13] and retinoblastoma, [14] where it can sensitize cancer cells to chemotherapy or radiotherapy.…”

Neuroblastoma stem cells – mechanisms of chemoresistance and histonedeacetylase inhibitors

“…Recently, we have found an increase in percentage of CD133+ NBL cells after their incubation with VPA in a dose that did not induce apoptosis [45] (see Fig 4). We showed that VPA induced death in NBL cells growing both under normoxic and hypoxic conditions and can overcome hypoxia induced resistance to cisplatin-induced apoptosis in HR NBL cells [70]. However, the question remains whether those changes are connected with hypoxic induction of CSCs, or whether VPA affects only more differentiated cells.…”