Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the β-Catenin/Tcf4 Interaction

Qinghao Zhang; Mei Gao; Guifen Luo; Xiaofeng Han; Wenjing Bao; Yanyan Cheng; Wang Tian; Maocai Yan; Guanlin Yang; Jing An

doi:10.1371/journal.pone.0152407

Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the β-Catenin/Tcf4 Interaction

PLoS One. 2016 Mar 25;11(3):e0152407. doi: 10.1371/journal.pone.0152407. eCollection 2016.

Authors

Qinghao Zhang^{1

2}, Mei Gao^{1

2}, Guifen Luo^{1

2}, Xiaofeng Han^{1

2}, Wenjing Bao^{1

2

3}, Yanyan Cheng^{1

2

3}, Wang Tian^{1

2}, Maocai Yan⁴, Guanlin Yang³, Jing An^{1

2

5}

Affiliations

¹ Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.
² SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.
³ Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China.
⁴ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
⁵ Department of Medicine, University of California San Diego, La Jolla, California, United States of America.

Abstract

Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of β-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index <1.0). Co-treatment with BC-23 at low concentrations effectively inhibits Wnt/β-catenin signaling and down-regulates c-Myc and cyclin D1 expression. S phase arrest and ROS generation are also involved in the enhancement of radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Binding, Competitive
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / therapy
Cell Cycle
Cell Line, Tumor / drug effects
Cell Line, Tumor / radiation effects
Cyclin D1 / metabolism
Down-Regulation
Gene Expression Regulation, Neoplastic
Humans
Luciferases / metabolism
Lung Neoplasms / metabolism*
Lung Neoplasms / therapy
Neoplastic Stem Cells / cytology
Nimustine / chemistry*
Proto-Oncogene Proteins c-myc / metabolism
Radiation Tolerance / drug effects*
Reactive Oxygen Species / metabolism
Spectrometry, Fluorescence
Transcription Factor 4
Transcription Factors / metabolism*
X-Rays
beta Catenin / metabolism*

Substances

Antineoplastic Agents
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
CCND1 protein, human
CTNNB1 protein, human
Proto-Oncogene Proteins c-myc
Reactive Oxygen Species
TCF4 protein, human
Transcription Factor 4
Transcription Factors
beta Catenin
Nimustine
Cyclin D1
Luciferases

Grants and funding

This work was supported in part by grants from the Connolly Endowment/Hendricks Fund and the LUNGevity Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.