Abstract
Multimodal oncological strategies which combine chemotherapy or radiotherapy with hyperthermia, have a potential of improving the efficacy of the non-surgical methods of cancer treatment. Hyperthermia engages the heat-shock response (HSR) mechanism, the main component of which are heat-shock proteins. Cancer cells have already partially activated HSR, thereby hyperthermia may be more toxic to them relative to normal cells. On the other hand, HSR triggers thermotolerance, i.e. hyperthermia-treated cells show an impairment in their susceptibility to a subsequent heat-induced stress. This poses questions about efficacy and optimal strategy for anti-cancer therapy combined with hyperthermia treatment. To address these questions, we adapt our previous HSR model and propose its stochastic extension. We formalize the notion of a HSP-induced thermotolerance. Next, we estimate the intensity and the duration of the thermotolerance. Finally, we quantify the effect of a multimodal therapy based on hyperthermia and a cytotoxic effect of bortezomib, a clinically approved proteasome inhibitor. Consequently, we propose an optimal strategy for combining hyperthermia and proteasome inhibition modalities. In summary, by a mathematical analysis of HSR, we are able to support the common belief that the combination of cancer treatment strategies increases therapy efficacy.
Highlights
Most of the non-surgical methods of cancer treatment are based on the principle of putting some kind of stress on cancer cells to induce their death
We developed a stochastic counterpart of the deterministic model, represented by the chemical master equation (CME) or, equivalently, continuous-time Markov chain (CTMC), which we analysed using the probabilistic model checking (PMC) technique
We formalized and quantified the notion of thermotolerance induced by the heat-shock proteins (HSPs)-based mechanism of heat-shock response (HSR)
Summary
Most of the non-surgical methods of cancer treatment (e.g. chemotherapy and radiotherapy) are based on the principle of putting some kind of stress on cancer cells to induce their death. The fact that heat-shock proteins (HSPs) prevent apoptosis induced by different modalities of cancer treatment explains how these proteins could limit the application of such anti-cancer therapies [1]. HSPs are a group of highly conserved proteins involved in many physiological and pathological cellular processes. They are the so-called chaperones, as they protect proteins from stress and help new and distorted proteins with folding into their proper shape [2]. Little is still known about how exactly HSPs are involved in different processes related to cancer development. We will denote the Hsp protein by HSP on
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