Original articleSkin toxicity following radiotherapy in patients with breast carcinoma: is anthocyanin supplementation beneficial?
Introduction
Adhesion to the Mediterranean diet reduces the risk of chronic degenerative diseases and of total mortality [1]. Bioactive polyphenols, of which fruit and vegetables contributing to the Mediterranean dietary pattern are particularly rich, possess antioxidant activities and contribute to reduce oxidative stress and to down-regulate the inflammatory response to injury. Within polyphenols, anthocyanins are a subclass of flavonoids, responsible for the red, purple and blue colors of plants and fruits, widely recognized for their anti-inflammatory and antioxidant properties [[2], [3], [4]].
In the frame of two EU-funded projects, FLORA (FLavonoids and related phenolics for healthy living using ORally recommended Antioxidants, STREP 007130) and ATHENA (AnTHocyanin and polyphenol bioactives for Health Enhancement through Nutritional Advancement, FP7-KBBE-2009-3), foods enriched in anthocyanins by genetic engineering or by genetic selection or classical breeding, have been tested in different experimental models and shown health-promoting activities against cardiovascular, cancer and neurodegenerative diseases [[5], [6], [7], [8]].
In healthy volunteers, four-week ingestion of anthocyanin-rich red orange juice resulted in measurable urine excretion of the main anthocyanin metabolites, but did not affect platelet activation nor cell inflammation markers of cardiovascular disease [9]. On the other hand, a single drink of orange juice prevented in human volunteers the post-prandial inflammatory response to a standardized fatty meal, a condition similar to a low-grade inflammatory status [10]. This finding is in keeping with the epidemiological observation that polyphenol intake was inversely associated with low-grade inflammation in the Moli-sani cohort [11].
Moving from healthy subjects and a general population to patients, moderate wine consumption was reported in a retrospective observational study to be protective from skin toxicity induced by radiotherapy (RT) in breast cancer patients; such effect was ascribed to the possible antioxidant activity of polyphenols contained in wine [12].
The skin response to ionizing radiation may involve multiple inflammatory outbreaks: vascular damage, with consequent thrombin generation, which induces circulating inflammatory cells to release cytokines; within the latter, the transforming growth factor (TGF)-β is responsible of dermal fibroblasts activation and skin fibrosis, interleukin (IL)-1 and tumor necrosis factor (TNF)-α stimulate metalloproteinase production and disruption of the basal cell layer, while adhesion molecules and TNF-α contribute to the inflammatory process. Anthocyanins have been shown to stimulate extracellular matrix proteins, such as collagen and elastin, in human skin fibroblasts [13]; to inhibit UV radiation-induced human dermal fibroblast injury by upregulating autophagy [14], to alter inflammatory cytokine release and actions and to blunt the excess of oxygen radicals generated by radiations [15].
The present trial was designed to test the possible beneficial effect on skin toxicity of anthocyanins derived from purple corn cobs in breast cancer patients undergoing RT [5].
Section snippets
Subjects and methods
This article conforms to the Consolidated Standards of Reporting Trials (CONSORT) consortium [16].
Participant flow
The eligible patients contacted, all of Caucasian ethnicity, were 242; of these, 25 refused to participate and 217 signed the informed consent. Twenty four patients dropped out before randomization and of the remaining 193 patients, 74 and 119 had been assigned to 3- and 5-week RT, respectively; the randomization to supplementation assigned 37 and 60 patients to anthocyanin (for the 3- and the 5-week RT groups, respectively), 37 and 59 to placebo supplement (for the 3- and the 5-week RT groups,
Discussion
The present study evaluated whether a chronic anthocyanin oral supplementation would favorably modify the local skin toxicity induced by RT in breast cancer patients.
Clinical trial registry number
clinicaltrial.gov ID: NCT02195960. https://clinicaltrials.gov/ct2/results?term=NCT02195960&Search=Search.
Financial support
The present study was partially supported by the EU FP7-KBBE-2009-3 ATHENA Project N. 245121, by the Italian AIRC "5xMILLE" Hypercan Study (N. 12237) and by the POR FESR 2014-2020, SATIN: Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti (DD n. 459 del 27/11/2018).
Data sharing
Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval by the EU-ATHENA trial Steering Committee.
Authorship
MBD, CT, CC, LI, AGM and GdG conceived the project and designed the research; MBD, CC, KP, LI developed the research plan and study design; FB, ADeC, CD, MB and GM conducted the research trial (patient recruitment and follow-up, outcome measurements, clinical and laboratory data collection); CT, KP and RP provided the original supplements, standardized, controlled and in large quantity, essential for the trial; ADiC and SCo analyzed data and performed statistical analysis; FD and SCi supervised
Conflict of interest
All Authors declare that they have no conflict of interest in relation to the present study.
Acknowledgements
This paper is dedicated to the memory of Cinzia Digesù, who enthusiastically contributed to this study design and its start.
We thank all the patients, who accepted to participate in the trial, the doctors, nurses and RT technicians of the Radiotherapy Unit for collaboration, and the personnel of the Laboratory of Analyses (director Dr. Stefano Papini) of the Gemelli Molise Hospital, Campobasso, Italy, for the laboratory test analyses.
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2022, Nutrition ResearchCitation Excerpt :Therefore, larger and better-designed interventional studies are necessary to help clarify some points of uncertainty related to anthocyanins in clinical treatment. In addition, it is noteworthy that an interventional study with 242 female BC patients addressed the beneficial effects of ARE intake from corn in preventing side effects of radiotherapy performed in BC treatment (NCT02195960, ClinicalTrials.gov) [47]. The principal aim of this study was to determine whether ARE from corn could prevent acute and long-term skin toxicity from radiotherapy in BC treatment.
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