Glutathione Depletion and Carbon Ion Radiation Potentiate Clustered DNA Lesions, Cell Death and Prevent Chromosomal Changes in Cancer Cells Progeny

Abstract

Poor local control and tumor escape are of major concern in head-and-neck cancers treated by conventional radiotherapy or hadrontherapy. Reduced glutathione (GSH) is suspected of playing an important role in mechanisms leading to radioresistance, and its depletion should enable oxidative stress insult, thereby modifying the nature of DNA lesions and the subsequent chromosomal changes that potentially lead to tumor escape.This study aimed to highlight the impact of a GSH-depletion strategy (dimethylfumarate, and l-buthionine sulfoximine association) combined with carbon ion or X-ray irradiation on types of DNA lesions (sparse or clustered) and the subsequent transmission of chromosomal changes to the progeny in a radioresistant cell line (SQ20B) expressing a high endogenous GSH content. Results are compared with those of a radiosensitive cell line (SCC61) displaying a low endogenous GSH level.DNA damage measurements (γH2AX/comet assay) demonstrated that a transient GSH depletion in resistant SQ20B cells potentiated the effects of irradiation by initially increasing sparse DNA breaks and oxidative lesions after X-ray irradiation, while carbon ion irradiation enhanced the complexity of clustered oxidative damage. Moreover, residual DNA double-strand breaks were measured whatever the radiation qualities. The nature of the initial DNA lesions and amount of residual DNA damage were similar to those observed in sensitive SCC61 cells after both types of irradiation. Misrepaired or unrepaired lesions may lead to chromosomal changes, estimated in cell progeny by the cytome assay. Both types of irradiation induced aberrations in nondepleted resistant SQ20B and sensitive SCC61 cells. The GSH-depletion strategy prevented the transmission of aberrations (complex rearrangements and chromosome break or loss) in radioresistant SQ20B only when associated with carbon ion irradiation. A GSH-depleting strategy combined with hadrontherapy may thus have considerable advantage in the care of patients, by minimizing genomic instability and improving the local control.

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

“…However, cancer cells also generate a large amount of intrinsic antioxidants such as GSH, superoxide dismutase and catalase to counteract ROS and tolerate ROS-induced oxidative stress, leading to altered redox balance 1,17 . In particular, a large amount of GSH is known to play a critical role in cellular redox maintenance and antioxidative systems 8,10 . We also found that DU145 cells have the highest level of GSH and H 2 O 2 and the least level of GSH and H 2 O 2 were observed with normal NIH3T3 cells † † † ** ** *** *** *** *** *** ( Supplementary Fig.…”

“…Accumulating evidence has suggested that abnormal cancer cells are under oxidative stress associated with an increased production of ROS due to disrupted ROS homeostasis and cancer cells have also adapted to oxidative stress by activating antioxidant systems often through the upregulation of glutathione (GSH) 2,[7][8][9][10] . Ironically, cancer cells are also known to utilize ROS to drive proliferation and other events required for tumour development 11,12 .…”

Cellular and molecular portrait of eleven human glioblastoma cell lines under photon and carbon ion irradiation

“…However, despite this induction of cell death, some tumor cells are capable of survival by undergoing endomitosis and reentering the cell cycle [23], and therefore can acquire a resistant phenotype [12,24]. However, as we have demonstrated that ceramide is an essential mediator in the course of late apoptosis activated during mitotic catastrophe, the modulation of this pathway will therefore be of interest in the future development of drugs in association with radiotherapy [25].…”

Effect of Seminal Transforming Growth Factorß1 (TGFß1) and Glutathione on Apoptosis in Spermatozoa from Tunisian Infertile Men

“…The limit of our study is to know the exact rate of TGFB1 from which the spermatozoa become highly altered and therefore utilizable for fertilization [18][19][20][21]57]. Therefore we recommended the evaluation of seminal status of TGFß1 before any attempt of assisted reproduction.…”

“…Subjects currently on any medication or antioxidant supplementation were not included [16][17][18][19][20][21][22][23][24]. In addition, subjects with testicular varicocele, genital infection, leukocytespermia, chronic illness and serious systemic diseases, smokers and alcoholic men were excluded from the study because of their well-known high seminal ROS levels and decreased antioxidant activity.…”