Adaptation to Chronic-Cycling Hypoxia Renders Cancer Cells Resistant to MTH1-Inhibitor Treatment Which Can Be Counteracted by Glutathione Depletion

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.

Relative biological effect of alpha particle radiation on low dose phenomena: lethal mutation, hyper-radiosensitivity and increased radioresistance

At high doses, the current recommended radiation weighting factors advise a significantly higher effectiveness of alpha particles relative to gamma radiation. However, at lower doses, the ratio of effectiveness between radiations of varying linear energy transfer values is complicated due to the relative importance of low dose phenomena such as genomic instability, bystander effects, low dose hyper-radiosensitivity and increased radioresistance (HRS/IRR). Radium is the most common source of alpha radiation exposure to humans, but the dosimetry is complicated by the decay chain which involves gamma exposure due to radon daughters. This study aimed to isolate the relative biological effect of alpha particles after low doses of radium to cells and their progeny. This was done by subtracting the survival values of a human keratinocyte cell line (HaCaT) and an embryonic Chinook salmon cell line (CHSE-214) exposed to gamma irradiation, from survival of the same cell lines exposed to mixed alpha and gamma radiation through chronic exposure to Ra-226 and its decay products. The human cell line showed increased radioresistance when exposed to low doses of alpha particles. In contrast the fish cell line, which demonstrated radioresistance to low dose gamma energy, demonstrated increased lethality when exposed to low doses of alpha particles. The results confirm the need to consider the dose-response relationship when developing radiation weighting factors for low dose exposures, as well as the need to be aware of possible cell line and species differences.