Protecting Healthy Cells Against the Negative Effects of Radiation Therapy for Lung Cancer

Abstract

Although radiation therapy is a commonly used treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory, antioxidant modulators primarily by inducing the Nrf2/ARE pathway. In the documented series of experiments, I show that CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, whereas CDDO-Me does not further protect cancer lines from radiation-induced cytotoxicity, nor does it protect experimentally transformed human bronchial epithelial cells with progressive oncogenic manipulations. Additionally, CDDO-Me protects human lymphocytes against radiation-induced DNA damage. As part of these studies other compounds (RTA-408, TA-65, and Yel-002) were also tested for radioprotective effects in epithelial and cancer cells as well as human lymphocytes. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, potentially resulting in better outcomes with less toxicity for patients. The effects of radiation and DNA damage in traditional two-dimensional (2D) cell culture conditions in vitro may not recapitulate tissue responses as modeled in three-dimensional (3D) organotypic culture systems since important signals, provided by the extracellular matrix and microenvironment, are lost in 2D monolayer cultures. While irradiating premalignant HBECs in traditional 2D culture significantly increased cancer progression phenotypes, irradiation in 3D culture reduced radiation-induced transformation compared to 2D. Furthermore, 3D cell culture conditions did not affect cell killing, the ability of cells to survive in a colony formation assay, and proliferation rates after radiation--implying there was no obvious selection against any cells in or dissociated from 3D conditions. My findings indicate that culture conditions are crucial for cellular responses to radiation and can affect cancer progression. If 3D culture is a more biologically representative model compared to 2D cultures, then current studies assessing transformation and radiation may be overestimating radiation risks using standard 2D culture methods.