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Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein.

Rao E, Singh P, Zhai X, Li Y, Zhu G, Zhang Y, Hao J, Chi YI, Brown RE, Cleary MP, Li B - Oncotarget (2015)

Bottom Line: Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation.Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages.Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNβ responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5-(benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

No MeSH data available.


Related in: MedlinePlus

EI-05 treatment inhibits mammary tumor growthE0771 tumor cells (0.5×106/mouse) were orthotopically injected into the mammary fat pad of C57B/C mice (n=20). Mice were randomly divided into two groups (n=10/group) and i.p. administered with either EI-05 (10 mg/kg) or vehicle DMSO control every other day. Tumors were measured at 3-day intervals and tumor growth curve were shown in panel (A). Representative tumor pictures in each group on day 27 after tumor injection were shown in panel (B). (C) Average tumor weights were measured on day 27 after mice were euthanized. (D) Flow cytometric analysis of tumor infiltrated F4/80+CD11c+ macrophages in EI-05- or DMSO-treated mice. Intracellular staining of the production of IFNγ (E) and Granzyme B (F) in tumor infiltrated CD8+ T cells from EI-05- or DMSO-treated mice (*, p < 0.05 as compared to the DMSO group).
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Figure 6: EI-05 treatment inhibits mammary tumor growthE0771 tumor cells (0.5×106/mouse) were orthotopically injected into the mammary fat pad of C57B/C mice (n=20). Mice were randomly divided into two groups (n=10/group) and i.p. administered with either EI-05 (10 mg/kg) or vehicle DMSO control every other day. Tumors were measured at 3-day intervals and tumor growth curve were shown in panel (A). Representative tumor pictures in each group on day 27 after tumor injection were shown in panel (B). (C) Average tumor weights were measured on day 27 after mice were euthanized. (D) Flow cytometric analysis of tumor infiltrated F4/80+CD11c+ macrophages in EI-05- or DMSO-treated mice. Intracellular staining of the production of IFNγ (E) and Granzyme B (F) in tumor infiltrated CD8+ T cells from EI-05- or DMSO-treated mice (*, p < 0.05 as compared to the DMSO group).

Mentions: To investigate the therapeutic efficacy of EI-05 for tumor treatment, we orthotopically inoculated mouse E0771 mammary tumor cells into the mammary fat pat of mice and measured the tumor growth in EI-05- or vehicle-treated mice. Very strikingly, tumor growth in EI-05-treated mice was significantly decreased in volume (about 40%) as compared to vehicle-treated group (Figure 6A). Accordingly, tumors in EI-05 treated mice exhibited reduced size and weight than those in control mice (Figure 6B, 6C). Interestingly, EI-05 treatment greatly increased the percentage of F4/80+CD11c+ TAMs in tumors (Figure 6D). It is worth noting that EI-05 administration also remarkably enhanced the production of IFNγ and Granzyme B by tumor-infiltrated CD8+ T cells (Figure 6E, 6F). Thus, these results suggest that EI-05 administration is able to inhibit mammary tumor growth, thus representing a novel drug candidate for anti-tumor treatment.


Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein.

Rao E, Singh P, Zhai X, Li Y, Zhu G, Zhang Y, Hao J, Chi YI, Brown RE, Cleary MP, Li B - Oncotarget (2015)

EI-05 treatment inhibits mammary tumor growthE0771 tumor cells (0.5×106/mouse) were orthotopically injected into the mammary fat pad of C57B/C mice (n=20). Mice were randomly divided into two groups (n=10/group) and i.p. administered with either EI-05 (10 mg/kg) or vehicle DMSO control every other day. Tumors were measured at 3-day intervals and tumor growth curve were shown in panel (A). Representative tumor pictures in each group on day 27 after tumor injection were shown in panel (B). (C) Average tumor weights were measured on day 27 after mice were euthanized. (D) Flow cytometric analysis of tumor infiltrated F4/80+CD11c+ macrophages in EI-05- or DMSO-treated mice. Intracellular staining of the production of IFNγ (E) and Granzyme B (F) in tumor infiltrated CD8+ T cells from EI-05- or DMSO-treated mice (*, p < 0.05 as compared to the DMSO group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: EI-05 treatment inhibits mammary tumor growthE0771 tumor cells (0.5×106/mouse) were orthotopically injected into the mammary fat pad of C57B/C mice (n=20). Mice were randomly divided into two groups (n=10/group) and i.p. administered with either EI-05 (10 mg/kg) or vehicle DMSO control every other day. Tumors were measured at 3-day intervals and tumor growth curve were shown in panel (A). Representative tumor pictures in each group on day 27 after tumor injection were shown in panel (B). (C) Average tumor weights were measured on day 27 after mice were euthanized. (D) Flow cytometric analysis of tumor infiltrated F4/80+CD11c+ macrophages in EI-05- or DMSO-treated mice. Intracellular staining of the production of IFNγ (E) and Granzyme B (F) in tumor infiltrated CD8+ T cells from EI-05- or DMSO-treated mice (*, p < 0.05 as compared to the DMSO group).
Mentions: To investigate the therapeutic efficacy of EI-05 for tumor treatment, we orthotopically inoculated mouse E0771 mammary tumor cells into the mammary fat pat of mice and measured the tumor growth in EI-05- or vehicle-treated mice. Very strikingly, tumor growth in EI-05-treated mice was significantly decreased in volume (about 40%) as compared to vehicle-treated group (Figure 6A). Accordingly, tumors in EI-05 treated mice exhibited reduced size and weight than those in control mice (Figure 6B, 6C). Interestingly, EI-05 treatment greatly increased the percentage of F4/80+CD11c+ TAMs in tumors (Figure 6D). It is worth noting that EI-05 administration also remarkably enhanced the production of IFNγ and Granzyme B by tumor-infiltrated CD8+ T cells (Figure 6E, 6F). Thus, these results suggest that EI-05 administration is able to inhibit mammary tumor growth, thus representing a novel drug candidate for anti-tumor treatment.

Bottom Line: Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation.Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages.Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNβ responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5-(benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

No MeSH data available.


Related in: MedlinePlus