Bcl-2/Bcl-xL inhibitor ABT-263 overcomes hypoxia-driven radioresistence and improves radiotherapy

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.

Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors

“…Ionizing radiation causes lethal lesions such as DNA double-strand breaks, thus activating a series of cellular damage responses [ 14 ]. The inability of sufficient repair triggers the intrinsic apoptotic pathway which is ultimately regulated by the antiapoptotic Bcl-2 proteins [ 15 , 16 , 17 ]. By upregulation of Bcl-2 proteins, the cell may retort to cellular stress.…”

Emerging actionable targets to treat therapy-resistant colorectal cancers

“…For example, ABT-737 has been shown to improve the response to oxaliplatin in a TP53wt/KRASmut background [60] . Both ABT-737 and WEHI-539 have been shown to lower the apoptotic threshold by increasing the mitochondrial priming, thus sensitizing resistant CRC cells to chemotherapy; also, Ch282-5 potentiated the response to oxaliplatin both in vitro and in vivo [61] . On the other hand, ABT-263 has been proven to overcome hypoxia-driven radioresistance and improve radiotherapy [62] .…”

“…Both ABT-737 and WEHI-539 have been shown to lower the apoptotic threshold by increasing the mitochondrial priming, thus sensitizing resistant CRC cells to chemotherapy; also, Ch282-5 potentiated the response to oxaliplatin both in vitro and in vivo [ 61 ] . On the other hand, ABT-263 has been proven to overcome hypoxia-driven radioresistance and improve radiotherapy [ 62 ] . Several BH-3 mimetics are currently being tested in clinical trials, even though not for CRC, but mainly for hematological malignancies and other solid tumors [ 59 ] .…”

The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer

“…In addition, inhibition of apoptosis induced by overexpression of antiapoptotic proteins is a core factor in acquiring multidrug resistance (MDR) in breast cancer ( 102 ). Increased expression of antiapoptotic proteins Bcl-2 and Bcl-xL in HCT116 cells under hypoxia and treatment with irradiation during severe hypoxia significantly improved cell survival scores, which could be ameliorated by Bcl-2 inhibitor ABT-263 ( 103 ). This result suggests that hypoxia can increase antiapoptotic proteins and thus resistance to treatment, but the specific mechanism of HIF-1α in this process remains to be explored.…”