Effects of Combination Treatments with Astaxanthin-Loaded Microparticles and Pentoxifylline on Intracellular ROS and Radiosensitivity of J774A.1 Macrophages

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.

The Role of Macrophages in Liver Fibrosis: New Therapeutic Opportunities

“…RIF is a serious long-term side effect that compromises respiratory, hepatic, intestinal, and urinary functions in cancer patients exposed to radiotherapy [ 69 ]. Its pathogenesis is still not fully understood, although it is known that macrophages have a central role in RIF for their ability to produce reactive oxygen species (ROS), and inflammatory molecules that in turn trigger the fibrotic pathways in injured tissues [ 70 ]. They showed [ 67 ] in vitro experiments that these microparticles were not cytotoxic for macrophage cells and could be taken up only by them.…”

“…Astaxanthin-loaded (ASX) microparticles inhibited the production of bioavailable TGF-β by interfering with the activity of intracellular convertases, a class of enzymes implicated in the post-translational processing and activation of numerous pro-proteins (e.g., TGF-β). Further, they demonstrated that the effects of astaxanthin-loaded microparticles could be further potentiated by combination treatment with pentoxifylline [ 70 ], a drug approved for the treatment of claudication as it has anti-inflammatory properties (e.g., inhibition of TNF-α production and signaling) and improves rheological properties of blood and wound healing [ 71 ]. Given in combination with ASX microparticles, that on their own inhibit active TGF-β release by targeted macrophages, might result in more effective treatments against inflammation and fibrosis.…”

Defective synaptic plasticity in a model of Coffin-Lowry Syndrome is rescued by simultaneously targeting PKA and MAPK pathways

“…To evaluate synergistic effects of dual drug treatments on LTF and RSK activation, we used a two-way ANOVA to assess the interaction between two treatment factors [26][27][28][29] . The significance of the combined-drug interaction was used to evaluate the null hypothesis that the combined effect of two drugs is merely additive (Fig.…”

“…3A, oval). To analyze whether NSC and rolipram acted synergistically, we performed a two-way ANOVA as suggested by Slinker (1998) and applied by multiple groups [27][28][29] . Two drugs are deemed to act synergistically if the F statistic for the interaction effect is less than the critical value of 0.05.…”

Redox Active Molecules in Cancer Treatments

“… Synthetic compounds, i.e., alkyl thiols [ 10 ], dimethyl sulfoxide [ 11 ], metformin and S63845 [ 12 ], the ruthenium complex [Ru(Phen) 3 ] 2+ [ 13 ], and copper-based compounds—Casiopeinas [ 14 ]. Different formulations, i.e., peptide fractions from germinated soybeans conjugated to Fe 3 O 4 nanoparticles [ 15 ] and astaxanthin microparticles in combination with pentoxifylline [ 16 ]. Proteins (aquaporins [ 17 ]) and nuclear factor erythroid-2-related factor 2 (NRF2) [ 8 ].…”