AT-101, a pan-Bcl-2 inhibitor, leads to radiosensitization of non-small cell lung cancer.

Abstract

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.

• Authors: Luigi Moretti, Bo Li, Kwang Woon Kim, Heidi Chen, Bo Lu
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 5 Issue 5 Pg. 680-7 (May 2010) ISSN: 1556-1380 [Electronic] United States
• PMID: 20354451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Proto-Oncogene Proteins c-bcl-2
• Radiation-Sensitizing Agents
• Gossypol
• gossypol acetic acid

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, radiation effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology, radiotherapy)
• Cell Proliferation (drug effects, radiation effects)
• Gamma Rays
• Gossypol (analogs & derivatives, pharmacology)
• Humans
• Immunoblotting
• Lung Neoplasms (drug therapy, pathology, radiotherapy)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay