Curcumol and <scp>FTY720</scp> synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways

Zhao, Mingri; Yang, Chaoying; Chai, Siyu; Yuan, Yijun; Zhang, Ji; Cao, Pengfei; Wang, Yanpeng; Xiao, Xiaojuan; Wu, Kunlu; Yan, Huiwen; Liu, Jing; Sun, Shuming

doi:10.1002/ptr.6968

Cited by 11 publications

(4 citation statements)

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“…It may be hypothesized that FTY720 could directly affect the recruitment of neutrophils and macrophages that express S1P receptors. FTY720 is a novel type of immunosuppressant derived from the ascomycete Cordyceps sinensis , which plays an important role in immunosuppression by inducing lymphocyte apoptosis and homing ( 41 , 42 ). Furthermore, it has been reported that rat spleen cells cultured with FTY720 displayed the typical characteristics of apoptosis, including disappearance of microvilli on the cell surface, concentration of chromatin and the formation of apoptotic bodies ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

Kang

Pan

et al. 2022

Int J Mol Med

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As the current clinical treatment of acetaminophen (APAP)-induced liver injury (AILI) has its limitations, new and effective treatment methods are required. Fingolimod (FTY720) is an immunosuppressive drug developed in recent years that has been shown to have a protective effect against ischemia/reperfusion liver injury. However, the role of FTY720 in AILI remains unclear. The aim of the present study was to determine whether FTY720 has a protective effect on AILI. AILI was induced using intraperitoneal injection of 300 mg/kg APAP in male C57BL/6J mice. Following APAP challenge, the mice were administered 5 mg/kg FTY720 for 30 min. Protein expression levels were measured using western blot analysis. Cell viability was examined using Cell Counting Kit-8 assays. mRNA levels were measured using reverse transcription-quantitative PCR. Inflammation levels were evaluated using immunohistochemistry. Cell death and reactive oxygen species levels were examined using immunofluorescence. Furthermore, laser scanning intravital microscopy was used to directly observe immune cell recruitment. APAP treatment increased the serum levels of alanine transaminase and aspartate transaminase at the 6- and 12-h time-points, suggesting liver tissue damage. However, FTY720 attenuated the liver injury induced by APAP by reducing the recruitment of immune cells and the release of pro-inflammatory cytokines and chemokines. FTY720 activated JAK2/STAT3 signaling and regulated the expression of BAX, BCL-2 and p65 to inhibit apoptosis and inflammation. In addition, compared with APAP treatment, the viability of primary hepatocytes treated with APAP and FTY720 was increased. Inhibition of JAK2/STAT3 signaling attenuated the protective, antioxidant effects of FTY720. In conclusion, FTY720 reduced liver injury by regulating the JAK2/STAT3 signaling pathway. This compound was capable of inhibiting oxidative stress to reduce hepatocyte death and the infiltration of neutrophils in the liver.

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Section: Discussionmentioning

confidence: 99%

FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

Kang

Pan

et al. 2022

Int J Mol Med

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“…The clinical specimens of HCC showed that resistance to lenvatinib was related to the STAT3 (signal transducers and activators of transcription 3) pathway [16]. Although curcumol could inhibit STAT3 in human cancers [17,18], it is not clear whether it can increase the sensitivity of lenvatinib in HCC. This study aims to investigate the effects of curcumol and lenvatinib on HCC cell proliferation, apoptosis, invasion, and migration, as well as their relationship with the STAT3 signaling pathway, to determine whether curcumol increases lenvatinib sensitivity in HCC.…”

Section: Introductionmentioning

confidence: 99%

Curcumol Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells

Wu,

Wang

2024

Discovery Medicine

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Background: Lenvatinib is an important molecular target drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the application of molecular targeted therapies for HCC also faces some challenges. Cumulative evidence has also shown that curcumol is a potential anti-HCC drug. Curcumol can be used as a chemosensitizer to enhance the antitumor effect of chemotherapeutic drugs. The purpose of our study is to explore the effect of curcumol combined with lenvatinib on HCC. Methods: The antitumor effects of curcumol or/and lenvatinib on Huh 7 cells of the HCC cell line were examined using the cell counting kit-8 (CCK-8) assay, colony formation assay, and transwell assay. For in vivo investigation, the effect on subcutaneous growth was also determined in nude mice. Changes in autophagy were determined by transmission electron microscope (TEM). Protein levels of apoptotic-related factors, epithelial mesenchymal transition (EMT)-related factors, autophagy factors, and Ncadherin and janus tyrosine kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) were examined by Western blot. Results: In this study, we found that curcumol or lenvatinib could promote HCC cell apoptosis in vitro and inhibit the growth of HCC tumors in vivo (curcumol or lenvatinib group compared with control group, p < 0.05). While combination with curcumol treatment could improve the effect of lenvatinib on promoting cell apoptosis of HCC in vitro and inhibiting the growth of HCC tumors in vivo (combination group compared with lenvatinib group, p < 0.05). Curcumol combined with lenvatinib could induce more autolysosome formation detected by TEM. Mechanically, curcumol or lenvatinib could increase the expression of Bcl-2-associated X protein (Bax), E-cadherin, UNC-51-like kinase 1 (ULK), and microtubule-associated protein 1 light chain 3 (LC3B) II/I, whereas it reduced the expression of B-cell lymphoma-2 (Bcl-2), JAK2/STAT3 (curcumol or lenvatinib group compared with control group, p < 0.05). Furthermore, combined with curcumol treatment could increase the expression of Bax, E-cadherin, ULK, and LC3B II/I, whereas it reduced the expression of Bcl-2, N-cadherin, and JAK2/STAT3 (combination group compared with lenvatinib group, p < 0.05). These findings suggest that curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells. Conclusion: Curcumol enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.

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“…Chronic myelogenous leukemia (CML) is derived from the neoplastic transformation of HSCs [6,7]. BCR-ABL1 transforms HSCs into CML stem cells (referred to here as LSCs), which then generates the development of a clonal myeloproliferative disease [8]. Therefore, the important regulators of the self-renewal of HSCs must be considered.…”

Section: Introductionmentioning

confidence: 99%

Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model

Yin¹,

Su²,

Ge³

et al. 2023

Int. J. Biol. Sci.

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BCR-ABL oncogene-mediated Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) is suggested to originate from leukemic stem cells (LSCs); however, factors regulating self-renewal of LSC and normal hematopoietic stem cells (HSCs) are largely unclear. Here, we show that RalA, a small GTPase in the Ras downstream signaling pathway, has a critical effect on regulating the self-renewal of LSCs and HSCs. A RalA knock-in mouse model (RalA Rosa26-Tg/+ ) was initially constructed on the basis of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) assay to analyze normal hematopoietic differentiation frequency using single-cell resolution and flow cytometry. RalA overexpression promoted cell cycle progression and increased the frequency of granulocyte-monocyte progenitors (GMPs), HSCs and multipotent progenitors (MPPs). The uniform manifold approximation and projection (UMAP) plot revealed heterogeneities in HSCs and progenitor cells (HSPCs) and identified the subclusters of HSCs and GMPs with a distinct molecular signature. RalA also promoted BCR-ABL-induced leukemogenesis and self-renewal of primary LSCs and shortened the survival of leukemic mice. RalA knockdown prolonged survival and promoted sensitivity to imatinib in a patient-derived tumor xenograft model. Immunoprecipitation plus single-cell RNA sequencing of the GMP population confirmed that RalA induced this effect by interacting with RAC1. RAC1 inhibition by azathioprine effectively reduced the self-renewal, colony formation ability of LSCs and prolonged the survival in BCR-ABL1-driven RalA overexpression CML mice. Collectively, RalA was detected to be a vital factor that regulates the abilities of HSCs and LSCs, thus facilitating BCR-ABL-triggered leukemia in mice. RalA inhibition serves as the therapeutic approach to eradicate LSCs in CML.

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Curcumol and FTY720 synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways

Cited by 11 publications

References 50 publications

FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

Curcumol Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells

Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model

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