TY - JOUR
T1 - AT-101, a Pan-Bcl-2 inhibitor, leads to radiosensitization of non-small cell lung cancer
AU - Moretti, Luigi
AU - Li, Bo
AU - Kim, Kwang Woon
AU - Chen, Heidi
AU - Lu, Bo
N1 - Funding Information:
This study was supported in part by NCI grant 1R01 CA125842-01A1 and DOD BC030542.
PY - 2010/5
Y1 - 2010/5
N2 - Introduction: Radiotherapy has a central role in the treatment of lung cancer. However, its effectiveness is often limited, in part, because of the defects in key apoptosis regulators, such as Bcl-2 family members, that contribute to cancer ability to evade apoptosis. In this study, we tested AT-101, a pan-Bcl-2 inhibitor, as a potential radiosensitizer in lung cancer. Methods and Results: Clonogenic assays were used to determine the radiosensitivity of multiple lung cancer cell lines. On the basis of their relative response to radiotherapy, lung cancer cells were stratified into two groups, and a representative cell line of each group was selected for more in-depth study: A549 (resistant) and HCC2429 (sensitive). The expression levels of antiapoptotic (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic (Bax, Bak, and Bid) Bcl-2 proteins were determined for each group. Although the levels of Bcl-2 and Mcl-1 were low for both groups, Bcl-XL expression was dramatically higher in A549, whereas almost not detected in HCC2429. The levels of Bax/Bak were 40% higher in HCC2429 compared with A549. When administered alone, AT-101 resulted in increased apoptosis in concentration-dependent manner against both groups, with enhanced activity in HCC2429 even at lower concentration. Furthermore, AT-101 promoted radiosensitivity of A549 and HCC2429 cells (p < 0.005). Consistent with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay findings, A549 cells required increased AT-101 dose to achieve a similar cytoxicity to HCC2429 cells. Conclusions: These investigations suggest that the Bcl-2 family may serve as effective therapeutic targets in lung cancer. Further clinical studies are warranted to assess the potential of AT-101 as an agent that enhances the therapeutic ratio of radiotherapy in lung cancer.
AB - Introduction: Radiotherapy has a central role in the treatment of lung cancer. However, its effectiveness is often limited, in part, because of the defects in key apoptosis regulators, such as Bcl-2 family members, that contribute to cancer ability to evade apoptosis. In this study, we tested AT-101, a pan-Bcl-2 inhibitor, as a potential radiosensitizer in lung cancer. Methods and Results: Clonogenic assays were used to determine the radiosensitivity of multiple lung cancer cell lines. On the basis of their relative response to radiotherapy, lung cancer cells were stratified into two groups, and a representative cell line of each group was selected for more in-depth study: A549 (resistant) and HCC2429 (sensitive). The expression levels of antiapoptotic (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic (Bax, Bak, and Bid) Bcl-2 proteins were determined for each group. Although the levels of Bcl-2 and Mcl-1 were low for both groups, Bcl-XL expression was dramatically higher in A549, whereas almost not detected in HCC2429. The levels of Bax/Bak were 40% higher in HCC2429 compared with A549. When administered alone, AT-101 resulted in increased apoptosis in concentration-dependent manner against both groups, with enhanced activity in HCC2429 even at lower concentration. Furthermore, AT-101 promoted radiosensitivity of A549 and HCC2429 cells (p < 0.005). Consistent with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay findings, A549 cells required increased AT-101 dose to achieve a similar cytoxicity to HCC2429 cells. Conclusions: These investigations suggest that the Bcl-2 family may serve as effective therapeutic targets in lung cancer. Further clinical studies are warranted to assess the potential of AT-101 as an agent that enhances the therapeutic ratio of radiotherapy in lung cancer.
KW - Apoptosis
KW - Bcl-2
KW - Lung cancer
KW - Radiotherapy
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U2 - 10.1097/JTO.0b013e3181d6e08e
DO - 10.1097/JTO.0b013e3181d6e08e
M3 - Article
C2 - 20354451
AN - SCOPUS:77951878281
SN - 1556-0864
VL - 5
SP - 680
EP - 687
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 5
ER -