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MnTE-2-PyP Inhibits Stat6 Activation and Reprograms Pro-Tumor M2 Macrophages to Anti-Tumor M1
cell activation and promote cancer cell growth. Activation of
118
Stat6, a key transcriptional regulator of M2 Mφ, is reduced
MnTE-2-PyP Inhibits Stat6 Activation and Reprograms Pro-Tumor M2 Macrophages to Anti-Tumor M1
the inhibitory role of MnTE on M2 Mφ. These studies highlight the pivotal role of ROS during M2 Mφ polarization and provide rationale for antioxidant treatment of breast cancer to reprogram TAM.
Brandon Griess1, Kaustubh Datta1, and Melissa TeohFitzgerald1 1
with MnTE treatment providing mechanistic rationale for
DOI: 10.1016/j.freeradbiomed.2017.10.131
University of Nebraska Medical Center, USA
Macrophages (Mφ) have high plasticity and can polarize along a spectrum of two extremes, the pro-inflammatory M1 Mφ and the immuno-suppressive M2 Mφ. In highly aggressive triple negative breast cancer, tumor associated Mφ (TAM) have a pro-tumor M2-like phenotype and are associated with disease progression and decreased survival. Thus, it is critical to develop strategies to reprogram TAM away from pro-tumor M2 Mφ toward anti-tumor M1 Mφ. Recently, a lipid peroxide scavenger displayed some efficacy to selectively inhibit M2 Mφ markers and cytokines. Little is known about the redox status of M1 and M2 Mφ, which could shed light on this phenomena. Our hypothesis is protumorigenic M2 Mφ possess a distinct profile of pro- and
119 Penta-azamacrocyclic SOD Mimetics Enhance Pharmacological Ascorbate Oxidation and Anticancer effects in an H2O2-dependent Manner Collin D. Heer1, Andrew B. Davis1, David B. Riffe1, Brett A. Wagner1, Kelly C. Falls1, Garry R. Buettner1, Robert A. Beardsley2, Dennis P. Riley2, Bryan G. Allen1, and Douglas R. Spitz1
anti-oxidant enzymes resulting in a different sensitivity to
1
ROS modulation versus the anti-tumor M1 Mφ. Our results
The University of Iowa, USA
2
Galera Therapeutics, USA
show M2 Mφ, derived from primary human monocytes, have a significant 20-30% reduction in intracellular ROS levels versus M1 Mφ by DCFH and DHE staining, as well as dramatically reduced extracellular H2O2 by ~70%. These
changes are due in part to a combination of decreased ROS producing enzymes, Nox2, Nox5, and the Nox accessory protein CYBA, and increased ROS scavenging enzymes, catalase, Gpx1/4, and Cu/ZnSOD, in M2 Mφ. These data suggest M2 Mφ have increased ROS metabolism versus M1 Mφ, which may provide an advantage in the oxidative tumor microenvironment. Additionally, increasing ROS with exogenous H2O2, lead to increased M2 markers and
decreased M1 markers implicating the oxidative tumor
microenvironment in promoting a M2-like TAM phenotype. Similarly, reducing the extracellular oxidation by EcSOD reexpression in MB231, a triple negative breast cancer cell line, inhibited the MB231-mediated increase in M2 Mφ markers and decrease in M1 Mφ markers. Treatment with Mn(III)
meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
(MnTE), a small molecule SOD mimetic, shown to have antitumor effects, increased M1 Mφ markers, IL-12b and CD86, while decreasing M2 Mφ markers, IL-10, CD163, and CD206. MnTE inhibited the ability of M2 Mφ to inhibit T
90
Lung cancer accounts for approximately one-fourth of cancer deaths worldwide; new therapeutic approaches are desperately needed. An emerging adjuvant therapy currently in clinical trials is pharmacological ascorbate (P-AscH‒). The anti-cancer effects of P-AscH‒ are a result of its oxidation, resulting in increased flux and steady-state levels of H2O2 in
tumors. P-AscH‒ oxidation can be catalyzed by transition
metal ions. P-AscH‒ has been shown to reduce Mn(III)porphyrin superoxide dismutase (SOD) mimetics, increasing the rate of P-AscH‒ oxidation and enhancing the anti-tumor effect of P-AscH‒. However, the ability of Mn(II)-containing SOD mimetics to enhance the anticancer effects of P-AscH‒ is unknown. The current study shows that Mn(II)-containing penta-azamacrocylic SOD mimetics GC4419 and GC4401 can enhance P-AscH‒ oxidation, as determined by increased oxygen consumption and steady-state concentrations of ascorbate radical in complete cell culture media. These mimetics also enhance the toxicity of P-AscH‒ in H292 and H1299 lung cancer cell lines. This enhanced P-AscH‒induced lung cancer cell killing was shown to be dependent on the catalytic activity of the SOD mimics and the subsequent generation of H2O2, as determined using
SfRBM 2017
118
Stat6, a key transcriptional regulator of M2 Mφ, is reduced
MnTE-2-PyP Inhibits Stat6 Activation and Reprograms Pro-Tumor M2 Macrophages to Anti-Tumor M1
the inhibitory role of MnTE on M2 Mφ. These studies highlight the pivotal role of ROS during M2 Mφ polarization and provide rationale for antioxidant treatment of breast cancer to reprogram TAM.
Brandon Griess1, Kaustubh Datta1, and Melissa TeohFitzgerald1 1
with MnTE treatment providing mechanistic rationale for
DOI: 10.1016/j.freeradbiomed.2017.10.131
University of Nebraska Medical Center, USA
Macrophages (Mφ) have high plasticity and can polarize along a spectrum of two extremes, the pro-inflammatory M1 Mφ and the immuno-suppressive M2 Mφ. In highly aggressive triple negative breast cancer, tumor associated Mφ (TAM) have a pro-tumor M2-like phenotype and are associated with disease progression and decreased survival. Thus, it is critical to develop strategies to reprogram TAM away from pro-tumor M2 Mφ toward anti-tumor M1 Mφ. Recently, a lipid peroxide scavenger displayed some efficacy to selectively inhibit M2 Mφ markers and cytokines. Little is known about the redox status of M1 and M2 Mφ, which could shed light on this phenomena. Our hypothesis is protumorigenic M2 Mφ possess a distinct profile of pro- and
119 Penta-azamacrocyclic SOD Mimetics Enhance Pharmacological Ascorbate Oxidation and Anticancer effects in an H2O2-dependent Manner Collin D. Heer1, Andrew B. Davis1, David B. Riffe1, Brett A. Wagner1, Kelly C. Falls1, Garry R. Buettner1, Robert A. Beardsley2, Dennis P. Riley2, Bryan G. Allen1, and Douglas R. Spitz1
anti-oxidant enzymes resulting in a different sensitivity to
1
ROS modulation versus the anti-tumor M1 Mφ. Our results
The University of Iowa, USA
2
Galera Therapeutics, USA
show M2 Mφ, derived from primary human monocytes, have a significant 20-30% reduction in intracellular ROS levels versus M1 Mφ by DCFH and DHE staining, as well as dramatically reduced extracellular H2O2 by ~70%. These
changes are due in part to a combination of decreased ROS producing enzymes, Nox2, Nox5, and the Nox accessory protein CYBA, and increased ROS scavenging enzymes, catalase, Gpx1/4, and Cu/ZnSOD, in M2 Mφ. These data suggest M2 Mφ have increased ROS metabolism versus M1 Mφ, which may provide an advantage in the oxidative tumor microenvironment. Additionally, increasing ROS with exogenous H2O2, lead to increased M2 markers and
decreased M1 markers implicating the oxidative tumor
microenvironment in promoting a M2-like TAM phenotype. Similarly, reducing the extracellular oxidation by EcSOD reexpression in MB231, a triple negative breast cancer cell line, inhibited the MB231-mediated increase in M2 Mφ markers and decrease in M1 Mφ markers. Treatment with Mn(III)
meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
(MnTE), a small molecule SOD mimetic, shown to have antitumor effects, increased M1 Mφ markers, IL-12b and CD86, while decreasing M2 Mφ markers, IL-10, CD163, and CD206. MnTE inhibited the ability of M2 Mφ to inhibit T
90
Lung cancer accounts for approximately one-fourth of cancer deaths worldwide; new therapeutic approaches are desperately needed. An emerging adjuvant therapy currently in clinical trials is pharmacological ascorbate (P-AscH‒). The anti-cancer effects of P-AscH‒ are a result of its oxidation, resulting in increased flux and steady-state levels of H2O2 in
tumors. P-AscH‒ oxidation can be catalyzed by transition
metal ions. P-AscH‒ has been shown to reduce Mn(III)porphyrin superoxide dismutase (SOD) mimetics, increasing the rate of P-AscH‒ oxidation and enhancing the anti-tumor effect of P-AscH‒. However, the ability of Mn(II)-containing SOD mimetics to enhance the anticancer effects of P-AscH‒ is unknown. The current study shows that Mn(II)-containing penta-azamacrocylic SOD mimetics GC4419 and GC4401 can enhance P-AscH‒ oxidation, as determined by increased oxygen consumption and steady-state concentrations of ascorbate radical in complete cell culture media. These mimetics also enhance the toxicity of P-AscH‒ in H292 and H1299 lung cancer cell lines. This enhanced P-AscH‒induced lung cancer cell killing was shown to be dependent on the catalytic activity of the SOD mimics and the subsequent generation of H2O2, as determined using
SfRBM 2017