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- Hansel, C, et al.
(författare)
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Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Tumor hypoxia and hypoxic adaptation of cancer cells represent major barriers to successful cancer treatment. We revealed that improved antioxidant capacity contributes to increased radioresistance of cancer cells with tolerance to chronic-cycling severe hypoxia/reoxygenation stress. We hypothesized, that the improved tolerance to oxidative stress will increase the ability of cancer cells to cope with ROS-induced damage to free deoxy-nucleotides (dNTPs) required for DNA replication and may thus contribute to acquired resistance of cancer cells in advanced tumors to antineoplastic agents inhibiting the nucleotide-sanitizing enzyme MutT Homologue-1 (MTH1), ionizing radiation (IR) or both. Therefore, we aimed to explore potential differences in the sensitivity of cancer cells exposed to acute and chronic-cycling hypoxia/reoxygenation stress to the clinically relevant MTH1-inhibitor TH1579 (Karonudib) and to test whether a multi-targeting approach combining the glutathione withdrawer piperlongumine (PLN) and TH1579 may be suited to increase cancer cell sensitivity to TH1579 alone and in combination with IR. Combination of TH1579 treatment with radiotherapy (RT) led to radiosensitization but was not able to counteract increased radioresistance induced by adaptation to chronic-cycling hypoxia/reoxygenation stress. Disruption of redox homeostasis using PLN sensitized anoxia-tolerant cancer cells to MTH1 inhibition by TH1579 under both normoxic and acute hypoxic treatment conditions. Thus, we uncover a glutathione-driven compensatory resistance mechanism towards MTH1-inhibition in form of increased antioxidant capacity as a consequence of microenvironmental or therapeutic stress.
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- Sanne, J. M., et al.
(författare)
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Contextualizing resilience indicators – comparable across organizations yet specific to context
- 2021
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Ingår i: Journal of Risk Research. - : Informa UK Limited. - 1366-9877 .- 1466-4461. ; 24:12, s. 1652-1667
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Tidskriftsartikel (refereegranskat)abstract
- In an increasingly complex and interdependent world, it has become increasingly difficult and costly to identify and protect systems, communities or organizations against all possible threats. Resilience approaches, however, provide capacities or abilities to respond to hazards and threats beyond existing scenarios and associated response plans, as well as learn from these disturbances and improve performance.Thus, resilience approaches provides increased capabilities for strengthening beyond traditional risk, crisis and business continuity approaches. However, there are inherent challenges of contextualizing resilience indicators for specific uses for specific critical infrastructures while also designing a comprehensive and multidimensional approach as well as for comparison across various infrastructures. Based upon the development and application of an indicator-based decision-support system for resilience in a Horizon 2020 project, we describe and analyse how we addressed such challenges, providing opportunities for improving resilience for drinking water supply and distribution in Sweden.The findings show the value of a modular approach, iterative indicator design processes with relevant stakeholders, the necessity to attend to their organizational processes, to the regulatory context as well as to the assignments, evaluation criteria and cognitive regimes among various target audiences. The approach is a useful methodology to achieve policy objectives for critical infrastructures from a systemic perspective, such as identifying and evaluating resilience, development of measures to increase resilience and the development of performance metric as well as facilitating information-sharing and training.
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