المؤلفون: Mao, Ping¹ (AUTHOR), Huang, Changhao¹ (AUTHOR), Li, Yuyu¹ (AUTHOR), Zhao, Yuanyi¹ (AUTHOR), Zhou, Sujin¹ (AUTHOR), Zhao, Zhenggang¹ (AUTHOR), Mu, Yunping¹ (AUTHOR), Wang, Lina¹ (AUTHOR), Li, Fanghong¹ (AUTHOR) fi@gdut.edu.cn, Zhao, Allan Z.¹ (AUTHOR) azzhao@gdut.edu.cn

المصدر: Biomedicine & Pharmacotherapy. Jan2023, Vol. 157, pN.PAG-N.PAG. 1p.

مصطلحات موضوعية: *ACUTE myeloid leukemia, *PHOSPHODIESTERASE inhibitors, *DNA replication, *MITOCHONDRIA, *DISEASE relapse

مستخلص: Acute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce the proliferation of AML cells, block DNA replication process, and increase AML cell death. Zl-n-91 also impeded the growth of subcutaneous xenograft and prolonged the survival of the MLL-AF9-driven AML model. Bioinformatic analysis revealed that elevated mitochondrial gene signatures inversely correlate with the survival of AML patients; and importantly, Zl-n-91 strongly suppressed the function of mitochondria. In addition, this PDE4 inhibitor induced alterations in multiple signaling pathways, including the reduction of β-catenin activity. Stimulation of the Wnt/β-catenin pathway could attenuate the inhibitory effect of Zl-n-91 on AML cell proliferation as well as mitochondrial function. Taken together, we revealed for the first time that targeting PDE4 activity could attenuate mitochondrial function through a Wnt/β-catenin pathway, which in turn would block the growth of AML cells. Specific PDE4 inhibitors can potentially serve as a new treatment modality for AML patients. [Display omitted] • PDE4 inhibition blocks AML development. PDE4 inhibitors may be used in treating AML. • AML patients with high mitochondrial signature are associated with poor survival. • PDE4 inhibition suppresses mitochondrial functions and Wnt/β-catenin signaling. • Attenuating AML growth by PDE4 inhibition is mediated by Wnt/β-catenin signaling. [ABSTRACT FROM AUTHOR]

المؤلفون: Li, Meirong¹ (AUTHOR), Lu, Mengmeng² (AUTHOR), Lai, Yunhao² (AUTHOR), Zhang, Xindan² (AUTHOR), Li, Yuyu² (AUTHOR), Mao, Ping² (AUTHOR), Liang, Zhicheng³ (AUTHOR), Mu, Yunping² (AUTHOR), Lin, Ying¹ (AUTHOR), Zhao, Allan Z.² (AUTHOR), Zhao, Zhenggang^1,2 (AUTHOR) zhaozg@gdut.edu.cn, Zhou, Sujin^1,2 (AUTHOR) zhousj@gdut.edu.cn, Li, Fanghong^1,2 (AUTHOR) fli@gdut.edu.cn

المصدر: Biomedicine & Pharmacotherapy. Sep2020, Vol. 129, pN.PAG-N.PAG. 1p.

مصطلحات موضوعية: *ACUTE leukemia, *SALMONELLA typhimurium, *LEUKEMIA inhibitory factor, *KILLER cells, *LEUKOCYTE count, *SALMONELLA food poisoning, *PRELEUKEMIA

مستخلص: As shown in the graphical abstract of this study, the attenuated strain of Salmonella , VNP20009, induces the apoptosis of acute leukemia cells by upregulated expression of apoptosis-promoting protein, Bax and cleaved caspase-3 to kill leukemia cells. Furthermore, the treatment of VNP20009 induced anti-tumor immune responses mediated by various cytokines & chemokines (IFN-γ, TNF-α, LIF, CXCL-10, CCL-2) and immune cells (NK cells, T lymphocytes, CD4+ IFN-γ+ and CD8+ IFN-γ+ effector T cells). VNP20009 activates the immune system, leading to the development of a strong and effective anti-tumor systemic response and tumor remission in acute leukemia. It may be applied as a stand alone or in combination with other therapies, to better treat acute leukemia or other hematologic malignancies. • The attenuated Salmonella , VNP20009, can effectively attenuate the growth of acute leukemia. • VNP20009 bacteria can significantly extend the survival of the AML-bearing mice. • VNP20009 bacteria are well tolerated by the acute leukemia bearing mice. • VNP20009 can potently induce apoptosis in cultured acute leukemia cells. • VNP20009 strongly activates native and adaptive immunity in MLL-AF9-derived AML mice. Acute leukemia is a common hematological malignancy. Despite recent promising progress, the prognosis of acute leukemia patients remains to be improved. New therapies are therefore still needed. Salmonella typhimurium has been shown to be highly effective as an anti-tumor agent in many solid cancer models, but it has not been applied in acute leukemia. Here, we report an attenuated Salmonella typhimurium strain, VNP20009, can induce apoptosis in multiple types of leukemia cells both in vivo and in vitro. Furthermore, VNP20009 significantly inhibited the proliferation of MLL-AF9-induced acute myeloid leukemia cells and prolonged the survival of the AML-carrying mice. VNP20009 restored the counts of white blood cell (WBC) and its five subsets in peripheral blood (PB) to near-physiological values, and elevated the levels of certain cytokines, such as tumor necrosis factor-α (TNF-α), leukemia inhibitory factor (LIF), interferon-γ (IFN-γ), chemokine C-X-C motif ligand-10 (CXCL-10) and C-C motif ligand-2 (CCL-2). Moreover, the ratio of immune cells, including natural killer cells (NKs), CD4+ Th1-type cells and CD8+ IFN-γ-producing effector T cells were highly upregulated in the AML mice treated with VNP20009. The results of the present study potentially provide an alternative therapeutic strategy for hematologic malignancies through boosting the innate and adaptive anti-tumor immunity. [ABSTRACT FROM AUTHOR]