Abstract
Hypoxia, a characteristic of most human solid tumors, is a major obstacle to successful radiotherapy. While moderate acute hypoxia increases cell survival, chronic cycling hypoxia triggers adaptation processes, leading to the clonal selection of hypoxia-tolerant, apoptosis-resistant cancer cells. Our results demonstrate that exposure to acute and adaptation to chronic cycling hypoxia alters the balance of Bcl-2 family proteins in favor of anti-apoptotic family members, thereby elevating the apoptotic threshold and attenuating the success of radiotherapy. Of note, inhibition of Bcl-2 and Bcl-xL by BH3-mimetic ABT-263 enhanced the sensitivity of HCT116 colon cancer and NCI-H460 lung cancer cells to the cytotoxic action of ionizing radiation. Importantly, we observed this effect not only in normoxia, but also in severe hypoxia to a similar or even higher extent. ABT-263 furthermore enhanced the response of xenograft tumors of control and hypoxia-selected NCI-H460 cells to radiotherapy, thereby confirming the beneficial effect of combined treatment in vivo. Targeting the Bcl-2 rheostat with ABT-263, therefore, is a particularly promising approach to overcome radioresistance of cancer cells exposed to acute or chronic hypoxia with intermittent reoxygenation. Moreover, we found intrinsic as well as ABT-263- and irradiation-induced regulation of Bcl-2 family members to determine therapy sensitivity. In this context, we identified Mcl-1 as a resistance factor that interfered with apoptosis induction by ABT-263, ionizing radiation, and combinatorial treatment. Collectively, our findings provide novel insights into the molecular determinants of hypoxia-mediated resistance to apoptosis and radiotherapy and a rationale for future therapies of hypoxic and hypoxia-selected tumor cell fractions.
Highlights
Tumor hypoxia is a common feature in human solid tumors
To examine the effect of cycling hypoxia, we employed Compared to HCT116 cells, non-selected and hypoxia-selected hypoxia-selected NCI-H460 cells that were established by expos- NCI-H460 cells hardly induced apoptosis following ABT-263 ing them to repeated cycles of severe hypoxia and intermittent treatment in normoxia or hypoxia (Fig. 2B and C, respectively), reoxygenation [18]
The combined therapy was effective in manner starting 48 h and clearly increasing 72 h after irradiation. normoxia and hypoxia in both, non-selected and hypoxia-selected Irradiation in hypoxic conditions resulted in significantly lower NCI-H460 cells
Summary
Tumor hypoxia is a common feature in human solid tumors. Chronic hypoxia develops when tumor grows around functional vessels that transport chemically bound oxygen. With increasing distance to the vessel, tumor cells become hypoxic due to diffusion-limited oxygen supply [1]. Occlusion of vessels results in hypoxia due to perfusion-limited oxygen supply. In turn, can activate angiogenesis resulting in the formation of new vessels and reoxygenation. Exposure to hypoxia activates several oxygen-sensitive signaling cascades leading to metabolic adaptation, increasing cell death threshold [5] and metastatic potential [6], which acounts for a worse response to radiochemotherapy and poor prognosis. Tumor hypoxia is known to cause resistance to therapeutic agents and to radiotherapy that relies on reactive oxygen species (ROS) production and the formation of irreparable DNA damage as a result of peroxidation events [7,8,9]
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