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.
Highlights
Acquired therapy-resistance of solid tumors remains a major obstacle for successful cancer cure
We demonstrated that the associated increased resistance to treatment with ionizing radiation (IR) could be overcome amongst others by inhibition of glutathione metabolism [6] or by inhibition of antioxidantassociated mitochondrial transport systems, leading to impaired cellular and mitochondrial redox homeostasis [8,9]
Our previous work revealed increased radiosensitivity of chronic cycling hypoxiaselected anoxia-tolerant cancer cells [6,26], which was linked to improved antioxidant capacity of anoxia-tolerant cancer cells [6,8,9]
Summary
Acquired therapy-resistance of solid tumors remains a major obstacle for successful cancer cure. The adverse tumor microenvironment (TME) represents an important factor for the development of resistance [1], in line with adaptation processes on single cancer cell level that drive malignant progression [2]. In the context of therapy resistance mediated by an adverse TME, reduced availability of oxygen (tumor hypoxia) represents an important driver of genomic instability, malignant progression, and development of resistance to conventional therapies, such as radiotherapy [4]. Adaptation of cancer cells to a chronically hypoxic microenvironment involves increased flexibility to maintain the cellular redox homeostasis and an enhanced antioxidant capacity as a consequence of metabolic reprogramming; this helps cancer cells to cope with oxidative stress induced by increased cellular levels of reactive oxygen species (ROS) [5]. Work from other groups corroborated that targeting metabolic reprogramming associated with increased GSH levels is a promising concept for radiosensitization of cancer cells [10,11]
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