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Abstract
Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines that, in turn, are the drivers of pro-fibrotic pathways. In a previous work, we showed that phagocytosis could be exploited to deliver the potent natural antioxidant astaxanthin specifically to macrophages. For this purpose, astaxanthin encapsulated into µm-sized protein particles could specifically target macrophages that can uptake the particles by phagocytosis. In these cells, astaxanthin microparticles significantly reduced intracellular ROS levels and the secretion of bioactive TGFβ and increased cell survival after radiation treatments. Here we show that pentoxifylline, a drug currently used for the treatment of muscle pain resulting from peripheral artery disease, amplifies the effects of astaxanthin microparticles on J774A.1 macrophages. Combination treatments with pentoxifylline and encapsulated astaxanthin might reduce the risk of RIF in cancer patients.
Highlights
Radiation-induced fibrosis (RIF) is the most common long-term complication in cancer radiotherapy, and it affects a significant proportion of the ~60% cancer patients that receive radiation as part of their therapeutic regimens [1]
The onset of RIF occurs between 1–4 months and 1–2 years after radiotherapy and it progresses in severity with time [2]
The role of this pro-inflammatory cytokine is central to fibrosis because it promotes fibroblasts recruitment, and local deposition of extracellular matrix components [12]. It inhibits the expression of antioxidant enzymes in target cells, further contributing to intracellular reactive oxygen species (ROS) accumulation [12]. Given these encouraging results and the outcomes of combination treatments with PTX and vitamin E discussed above, we explored whether PTX could enhance the effects of ASX when given in combination to macrophages
Summary
Radiation-induced fibrosis (RIF) is the most common long-term complication in cancer radiotherapy, and it affects a significant proportion of the ~60% cancer patients that receive radiation as part of their therapeutic regimens [1]. PTX has been investigated as a radioprotector in vitro and in vivo because it can increase blood flow and tissue oxygenation upon oral administration [8] It has provided satisfactory results in terms of RIF resolution but only at high doses (i.e., 800 mg/day over a 6-month treatment period [8]) that are not tolerated by patients and that can cause, among the side effects, serious gastrointestinal disorders [8,9]. ASX microparticles significantly reduced intracellular ROS levels and, importantly, the secretion of bioactive transforming growth factor β (TGFβ) [11] The role of this pro-inflammatory cytokine is central to fibrosis because it promotes fibroblasts recruitment, and local deposition of extracellular matrix components [12]. We found that PTX could improve the antioxidant and radio-protective activities of ASX microparticles
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