Abstract
BACKGROUND AND OBJECTIVE. Hyperthermia is a promising modality for cancer treatment that urgently requires detailed knowledge on molecular and cellular processes for the rational development of treatment protocols. The thorough study of the response of the inner membrane of heart and liver mitochondria to hyperthermia was performed in order to establish the pattern of the hyperthermia-induced changes in the membrane barrier function. MATERIAL AND METHODS. The isolated mitochondria from rat heart and liver (of both genders) were used for experiments, as well as mitochondria isolated from the perfused male rat liver. Changes in the membrane permeability were evaluated by mitochondrial respiration in state 2 or by estimation of the modular kinetics of the membrane leak. RESULTS. The inner membrane of isolated mitochondria from healthy tissues was found to be an extremely sensitive target of hyperthermia that exerted the response even in the febrile range. More severe hyperthermia compromised the inner mitochondrial membrane function; however, this response was tissue-specific and, to some extent, gender-dependent (for liver mitochondria). The data obtained by direct heating of isolated mitochondria were validated by experiments on the perfused liver. CONCLUSIONS. The obtained results imply a crucial importance of the evaluation of the tissue- and gender-specific differences while developing or improving the protocols for hyperthermic treatment or combinatory therapy.
Highlights
Hyperthermia may be considered as a separate modality for cancer treatment, it is especially recognized for its synergistic action with the conventional cancer therapies such as radiation and chemotherapy
Bearing in mind that the rate of mitochondrial respiration in metabolic state 2 (V2) is almost entirely determined by the membrane permeability [16], the membrane permeability was evaluated by the measurement of V2 (Fig. 2) and in some cases, when an increase in V2 may be masked by inhibition of the respiratory module, by performing modular kinetics analysis
The obtained results indicated that an increase in temperature from 37°C to 40°C had no effect on respiratory rate in state 2 (V2) in isolated rat heart mitochondria (Fig. 2 and Table 1)
Summary
Hyperthermia may be considered as a separate modality for cancer treatment, it is especially recognized for its synergistic action with the conventional cancer therapies such as radiation and chemotherapy. It is important to establish thresholds for thermal damage in human tissues that vary among tissue species as well as among healthy and diseased tissues [4]. Induced thermal damages in the healthy organs set certain limits for the application of hyperthermia, in particular, for the whole body hyperthermia. Mild hyperthermic conditions in the healthy liver tissue are created around the central coagulative zone during thermoablation of hepatic tumors [5,6,7] and during catheter radiofrequency ablation in the heart, which is considered a standard therapy for a wide variety of cardiac arrhythmias [8]
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