The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand potent radioprotectants/radiomitigators. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of hemoprotein into the cytosol and commitment to the apoptotic program. Here we design and synthesize mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic and stearic acids which blocked peroxidase activity of cytochrome c/cardiolipin complex by specifically binding to its heme-iron. We show that both compounds inhibit pro-apoptotic oxidative events, suppress cyt c release, prevent cell death, and protect mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of imidazole-substituted oleic acid are observed after pretreatment of mice from 1 hr before through 24 hrs after the irradiation.
Purpose: Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the d and g isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kd/g inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Experimental Design: Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. Results: In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kd/g-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%-76%). Conclusions: Our results support PI3Kd/g inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.
Among the distinct molecular signatures present in the mitochondrion is
the tetra-acylated anionic phospholipid cardiolipin, a lipid also present in
primordial, single-cell bacterial ancestors of mitochondria and multiple
bacterial species today. Cardiolipin is normally localized to the inner
mitochondrial membrane; however, when cardiolipin becomes externalized to the
surface of dysregulated mitochondria, it promotes inflammasome activation and
stimulates the elimination of damaged or nonfunctional mitochondria by
mitophagy. Given the immunogenicity of mitochondrial and bacterial membranes
that are released during sterile and pathogen-induced trauma, we hypothesized
that cardiolipins might function as “eat me” signals for
professional phagocytes. In experiments with macrophage cell lines and primary
macrophages, we found that membranes with mitochondrial or bacterial
cardiolipins on their surface were engulfed through phagocytosis, which depended
on the scavenger receptor CD36. Distinct from this process, the copresentation
of cardiolipin with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide
dampened TLR4-stimulated production of cytokines. These data suggest that
externalized, extracellular cardiolipins play a dual role in host-host and
host-pathogen interactions by promoting phagocytosis and attenuating
inflammatory immune responses.
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