Targeting HSP70 induced thermotolerance for design of thermal sensitizers

Abstract

Thermal therapy has been shown to be an extremely powerful anti-cancer agent and a potent radiation sensitizer. However, the full potential of thermal therapy is hindered by a number of considerations including highly conserved heat resistance pathways in tumour cells and inhomogeneous heating of deep-seated tumours due to energy deposition and perfusion issues. This report reviews recent progress in the development of hyperthermia sensitizing drugs designed to specifically amplify the effects of hyperthermia. Such agents might be particularly useful in situations where heating is not adequate for the full biological effect or is not homogeneously delivered to tumours. The particular pathway concentrated on is thermotolerance, a complex, inducible cellular response that leads to heat resistance. This paper will concentrate on the molecular pathways of thermotolerance induction for designing inhibitors of heat resistance/thermal sensitizers, which may allow the full potential of thermal therapy to be utilized.

Optimization of maghemite-loaded PLGA nanospheres for biomedical applications

“…4 More recently, in order 3 to overcome the above-mentioned limitations, biocompatible magnetic nanoparticles have been proposed as a material basis to support the development of hyperthermia. 5 For MNPs based hyperthermia, a general procedure involves the distribution of particles throughout the targeted tumor site followed by generation of heat in to the tumor using an applied magnetic field.…”

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals

“…Intracellular heat shock protein (HSP) 72 accumulation improves heat tolerance through cytoprotective effects (22,37) such as the reduction of heat-induced cellular apoptosis (60) and protection against ischemia-reperfusion injury (42), yet limited data exist examining differences in HSP72 expression within monocyte subsets (4,53). In contrast with intracellular expression, extracellular (e)HSPs have been suggested to act as a "danger signal," activating immunecompetent cells (33) through similar LPS TLR-4/CD14-depen-dent signaling (2,3,8,17,44). Reduced CD14 ϩ CD16 ϩ inflammatory profiles (81) as well as a greater increase in HSP72 expression (60) and increased heat shock factor (HSF)-1 DNA binding affinity (43) have been related to training adaptations.…”

Thermosensitization of tumor cells with inhibitors of chaperone activity and expression

“…Так, Akimoto с соавторами [25] показали, что обработка радициколом прогретых клеток опухоли пищевода подавляет БТШ90-зависимую активацию Raf-1, p42/p44 Erk и Akt; прерывание этих антиапоптотических сигнальных каскадов может усилить клеточную гибель. Здесь важно, что повышение внутриклеточного содержания БТШ70 и БТШ27 тоже защищает от апоптоза [6,8,9]; следовательно, искусственная блокада индукции этих шаперонов в опухолевых клетках еще сильнее повысит вероятность их апоптотической гибели после гипертермии.…”

“…Кроме того, БТШ90, БТШ70 и БТШ27 известны как супрессоры апоптоза [6,7]. Клетка с повышенным содержанием БТШ способна пережить более сильный стресс, чем клетка с нормальным (конститутивным) уровнем БТШ [7][8][9].…”

“…БТШ и HSF1 часто рассматриваются как молекулярные мишени для сенсибилизации опухолей [8][9][10]. Особенно большое внимание уделяется БТШ90: этот конститутивно экспрессируемый шаперон необходим для созревания и активации рецепторов факторов роста и компонентов сигнальных каскадов, обеспечивающих неограниченное размножение раковых клеток и их устойчивость к терапии [11][12][13][14].…”