Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo

Mita, Toshihiro; Hirai, Makoto; Maki, Yoshiko; Nahar, Saifun; Yoshida, Naoko; Oshima, Yoshiteru; Kikuchi, Haruhisa; Kubohara, Yuzuru

doi:10.1016/j.bcp.2021.114834

Cited by 4 publications

(5 citation statements)

References 28 publications

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“…DIF-1 at 10 or 20 µM dose-dependently increased the rate of glucose consumption, consistent with our previous report [23], in confluent 3T3-L1 cells (Figure 2A), whereas no dose dependence was observed with 40 µM DIF-1 (Figure 2A). As far as cell morphology is concerned, no cytotoxicity of DIF-1 was observed within the dose range examined (Figure 2B); note that most cells (>95%) remained viable after 24 h incubation with 100 µM DIF-1 [31]. DIF-1 at 10-40 µM dose-dependently suppressed cell growth in 3T3-L1 cells (Figure 2C,D), as expected from previous reports [18,32].…”

Section: Effects Of Dif-1 On Glucose Uptake and Cell Growth In 3t3-l1...supporting

confidence: 86%

“…Molecules 2023, 28, x FOR PEER REVIEW 3 of 14 dose range examined (Figure 2B); note that most cells (>95%) remained viable after 24 h incubation with 100 µM DIF-1 [31]. DIF-1 at 10-40 µM dose-dependently suppressed cell growth in 3T3-L1 cells (Figure 2C,D), as expected from previous reports [18,32].…”

Section: Effects Of Dif-1 On Glucose Uptake and Cell Growth In 3t3-l1...supporting

confidence: 85%

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Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells

Kubohara,

Fukunaga,

Kikuchi

et al. 2023

Molecules

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Differentiation-inducing factor 1 (DIF-1) isolated from the cellular slime mold Dictyostelium discoideum can inhibit mammalian calmodulin-dependent cAMP/cGMP phosphodiesterase (PDE1) in vitro. DIF-1 also promotes glucose uptake, at least in part, via a mitochondria- and AMPK-dependent pathway in mouse 3T3-L1 fibroblast cells, but the mechanism underlying this effect has not been fully elucidated. In this study, we investigated the effects of DIF-1 on intracellular cAMP and cGMP levels, as well as the effects that DIF-1 and several compounds that increase cAMP and cGMP levels have on glucose uptake in confluent 3T3-L1 cells. DIF-1 at 20 μM (a concentration that promotes glucose uptake) increased the level of intracellular cAMP by about 20% but did not affect the level of intracellular cGMP. Neither the PDE1 inhibitor 8-methoxymethyl-3-isobutyl-1-methylxanthine at 10–200 μM nor the broad-range PDE inhibitor 3-isobutyl-1-methylxanthine at 40–400 μM had any marked effects on glucose uptake. The membrane-permeable cAMP analog 8-bromo-cAMP at 200–1000 μM significantly promoted glucose uptake (by 20–25%), whereas the membrane-permeable cGMP analog 8-bromo-cGMP at 3–100 μM did not affect glucose uptake. The adenylate cyclase activator forskolin at 1–10 μM promoted glucose uptake by 20–30%. Thus, DIF-1 may promote glucose uptake by 3T3-L1 cells, at least in part, via an increase in intracellular cAMP level.

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Section: Effects Of Dif-1 On Glucose Uptake and Cell Growth In 3t3-l1...supporting

confidence: 86%

Section: Effects Of Dif-1 On Glucose Uptake and Cell Growth In 3t3-l1...supporting

confidence: 85%

Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells

Kubohara,

Fukunaga,

Kikuchi

et al. 2023

Molecules

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“…The antiproliferative and antimigratory activities of DIF-3 (+1) and Bu-DIF-3 are comparatively strong in both cell lines ( Table 1 ); therefore, DIF-3 (+1) and Bu-DIF-3 may be good lead compounds for the development of antiproliferative and antimetastatic agents. On the other hand, the antiproliferative and antimigratory activities of DIF-1 (+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one) are weak in both cell lines ( Table 1 ), but as this derivative has strong antimalarial activity 45) , we used it for subsequent comparative analyses. In this study, we reconfirmed the effects of these DIF compounds on cell proliferation and morphology in MDA-MB-231 cells ( Figure 2 ), where we used DIF-1, Br-DIF-1, DIF-1 (+2), DIF-3, and DIF-3 (+1) at 20 μ M and Bu-DIF-3 at 10 μ M since Bu-DIF-3 at more than 10 μ M is highly toxic to the cell.…”

Section: Resultsmentioning

confidence: 99%

“…Herein, we assessed the effects of DIF-1 (+2) on the expression of cyclins D1 and D3 and PD-L1/PD-L2 in MDA-MB-231 cells, as DIF-1 (+2) has antimalarial activity 45) . The only significant biological activity of DIF-1 (+2) in these cells was a significant increase in PD-L1 low ( Figure 5C ).…”

Section: Discussionmentioning

confidence: 99%

<i>Dictyostelium</i> Differentiation-inducing Factor Derivatives Reduce the Glycosylation of PD-L1 in MDA-MB-231 Human Breast Cancer Cells

HIRAYAMA

Ishigaki

Takahashi

et al. 2023

Juntendo Medical Journal

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Objectives Triple-negative breast cancer (TNBC) is a metastatic and intractable cancer with limited treatment options. Refractory cancer cells often express the immune checkpoint molecules programmed death-ligand 1 (PD-L1) and PD-L2, which inhibit the anticancer effects of T cells. Differentiation-inducing factors, originally found in Dictyostelium discoideum , and their derivatives possess strong antiproliferative activity, at least in part by reducing cyclin D1 expression in various cancer cells, but their effects on PD-L1/PD-L2 have not been examined. In this study, we investigate the effects of six DIF compounds (DIFs) on the expression of PD-L1/PD-L2 and cyclin D1/D3 in MDA-MB-231 cells, a model TNBC cell line. Methods MDA-MB-231 cells were incubated for 5 or 15 h with or without DIFs, and the mRNA expression of cyclin D1, PD-L1, and PD-L2 were assessed by quantitative polymerase chain reaction (qPCR). Whereas, MDA-MD-231 cells were incubated for 12 or 24 h with or without DIFs, and the protein expression of cyclins D1 and D3, PD-L1, and PD-L2 were assessed by Western blotting. Results As expected, some DIFs strongly reduced cyclin D1/D3 protein expression in MDA-MB-231 cells. Contrary to our expectation, DIFs had little effect on PD-L1 mRNA expression or increased it transiently. However, some DIFs partially reduced glycosylated PD-L1 and increased non-glycosylated PD-L1 in MDA-MB-231 cells. The level of PD-L2 was very low in these cells. Conclusions Since PD-L1 glycosylation plays an important role in preventing T cells from attacking cancer cells, such DIFs may promote T cell attack on cancer cells in vivo .

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“…Yin E, Fukuhara T, Takeda K, Kojima Y, Fukuhara K, Ikejima K, Bashuda H, Kitaura J, Yagita H, Okumura K, Uchida K: Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury. SciRep, 2021;11: 6312. 4) Ishikawa T, Kageyama S, Miyahara Y, Okayama T, Kokura S, Wang L, Sato E, Yagita H, Itoh Y, Shiku H: Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients.…”

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Publications from Juntendo University Graduate School of Medicine, 2021 [6/6]

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Derivatives of Dictyostelium differentiation-inducing factors suppress the growth of Plasmodium parasites in vitro and in vivo

Cited by 4 publications

References 28 publications

Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells

Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells

<i>Dictyostelium</i> Differentiation-inducing Factor Derivatives Reduce the Glycosylation of PD-L1 in MDA-MB-231 Human Breast Cancer Cells

Publications from Juntendo University Graduate School of Medicine, 2021 [6/6]

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