Abstract
Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.
Highlights
Therapeutic management of cancer improved during the past decade and is characterized today by a significant increase in patient’s survival rates
Fibrosis contributes to the loss of intestinal compliance and impaired intestinal function and we showed that it was associated with heavy deposition of Connective Tissue Growth Factor (CTGF/ CCN2) [7]
In order to investigate whether the Rho/ Rho-associated kinases (ROCKs) cascade regulates radiation-induced fibrogenic program in intestinal mesenchymal cells, pharmacological inhibition of Rho and ROCK activation was performed in vitro using pravastatin and Y-27632, a pyrimidine derivative inhibitor of ROCK. We showed that both agents modulated radiation-induced fibrogenic differentiation and the expression of CTGF, TGF-b1, and collagen Ia2 genes (Figure 1), most likely via NFB inhibition [10,11,18]
Summary
Therapeutic management of cancer improved during the past decade and is characterized today by a significant increase in patient’s survival rates. The relevance of this study to fibrosis is unclear since only short term response was investigated, we aimed at investigating the role of combined pentoxifylline-vitamin E on two well know fibrogenic pathway, i.e. TGF-b1 and Rho/Rock using an in vitro model of radiation-induced fibrosis consisting of primary smooth muscle cells derived from human radiation enteropathy samples (RE-SMC). Incubation of the cells with combined pentoxifylline-trolox didn’t regulate RhoB mRNA expression (Figure 2A) nor influence Actin cytoskeleton in RE-SMC (data not shown) but interestingly negatively modulated TGF-b1 mRNA expression at early time point (one hour post-treatment) and subsequently decrease the expression of TGF-b1 targets such as PAI-1 both at mRNA and protein levels (twenty four hours post-treatment) (Figure 2A and 2B) This suggested that the anti-fibrotic effects of combined pentoxifyllinetrolox could be mediated by inhibition of the TGF-b1 pathway. Inhibition of TGF-b1 pathway is unlikely to be the sole anti-fibrotic mechanism of action of combined pentoxifylline-trolox and other novel candidates are under investigations
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