Abstract
Ethanol has been shown to exhibit therapeutic properties as an ablative agent alone and in combination with thermal ablation. Ethanol may also increase sensitivity of cancer cells to certain physical and chemical antitumoral agents. The aim of our study was to assess the potential influence of nontoxic concentrations of ethanol on hyperthermia therapy, an antitumoral modality that is continuously growing and that can be combined with classical chemotherapy and radiotherapy to improve their efficiency. Human leukemia cells were included as a model in the study. The results indicated that ethanol augments the cytotoxicity of hyperthermia against U937 and HL60 cells. The therapeutic benefit of the hyperthermia/ethanol combination was associated with an increase in the percentage of apoptotic cells and activation of caspases-3, -8 and -9. Apoptosis triggered either by hyperthermia or hyperthermia/ethanol was almost completely abolished by a caspase-8 specific inhibitor, indicating that this caspase plays a main role in both conditions. The role of caspase-9 in hyperthermia treated cells acquired significance whether ethanol was present during hyperthermia since the alcohol enhanced Bid cleavage, translocation of Bax from cytosol to mitochondria, release of mitochondrial apoptogenic factors, and decreased of the levels of the anti-apoptotic factor myeloid cell leukemia-1 (Mcl-1). The enhancement effect of ethanol on hyperthermia-activated cell death was associated with a reduction in the expression of HSP70, a protein known to interfere in the activation of apoptosis at different stages. Collectively, our findings suggest that ethanol could be useful as an adjuvant in hyperthermia therapy for cancer.
Highlights
The cells were cultured in absence or presence of ethanol (0.25%, 0.5%, and 1%) for 1 h and the cells were subjected to mild hyperthermia (30 min at 43 ◦ C)
As shown (Figure 1A), a clear decrease in the MTT reduction was observed in the cells exposed to hyperthermia alone and the decrease in mitochondrial activity was more evident in the cells exposed to hyperthermia in combination with increasing concentrations of ethanol
The results presented demonstrate that ethanol enhances apoptotic cell death in U937 and HL60 leukemia cells exposed to hyperthermia
Summary
Radiotherapy, and immunotherapy but despite the efforts and efficacy of these strategies mortality rates are still very high [1,2]. Most anticancer drugs and radiotherapy cause the death of sensitive cells by inducing apoptosis [3]. This kind of cell death can occur with or without the activation of caspases, a family of aspartate specific cysteine proteases which are generally synthesized as zymogens and activated by proteolytic cleavage [4]. There are two major caspase activation pathways [5]. The extrinsic pathway involves activation of cell surface death receptors Fas, death receptors 4 and 5
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