2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis

Hosang, Leon; Löhndorf, Anke; Döhle, Wolfgang; Rosche, Anette; Marry, Stephen; Diercks, Björn‐Philipp; Müller-Kirschbaum, Lukas C.; Flügel, Lioba T.; Potter, Barry V. L.; Odoardi, Francesca; Guse, Andreas H.; Flügel, Alexander

doi:10.1016/j.bbamcr.2023.119485

Cited by 5 publications

(2 citation statements)

References 47 publications

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“…Also, STX140 showed efficacy when administered orally in both MCF-7 WT and MCF-7 DOX breast cancer xenograft models, in contrast to paclitaxel and 2-methoxyestradiol [23]. Currently, there are no clinical trials ongoing with STX140, but the compound has already shown many promising results in preclinical studies in oncology [31,32] and also elsewhere, in particular its recent in vivo activity on preventing experimental autoimmune encephalitis [33].…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

Franco

Moraes

Carvalho

et al. 2023

IJMS

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The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment.

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Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

Franco

Moraes

Carvalho

et al. 2023

IJMS

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“…Interfering with the Ca 2+ signaling cascade has potential therapeutic effects. For example, blocking SOCE by STX140 efficiently ameliorates the course of disease in a rat model of multiple sclerosis, where it prevents immune cells from infiltrating the central nervous system ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation

Brock,

Lory,

Möckl

et al. 2024

Front. Immunol.

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CD8+ T cells are a crucial part of the adaptive immune system, responsible for combating intracellular pathogens and tumor cells. The initial activation of T cells involves the formation of highly dynamic Ca2+ microdomains. Recently, purinergic signaling was shown to be involved in the formation of the initial Ca2+ microdomains in CD4+ T cells. In this study, the role of purinergic cation channels, particularly P2X4 and P2X7, in CD8+ T cell signaling from initial events to downstream responses was investigated, focusing on various aspects of T cell activation, including Ca2+ microdomains, global Ca2+ responses, NFAT-1 translocation, cytokine expression, and proliferation. While Ca2+ microdomain formation was significantly reduced in the first milliseconds to seconds in CD8+ T cells lacking P2X4 and P2X7 channels, global Ca2+ responses over minutes were comparable between wild-type (WT) and knockout cells. However, the onset velocity was reduced in P2X4-deficient cells, and P2X4, as well as P2X7-deficient cells, exhibited a delayed response to reach a certain level of free cytosolic Ca2+ concentration ([Ca2+]i). NFAT-1 translocation, a crucial transcription factor in T cell activation, was also impaired in CD8+ T cells lacking P2X4 and P2X7. In addition, the expression of IFN-γ, a major pro-inflammatory cytokine produced by activated CD8+ T cells, and Nur77, a negative regulator of T cell activation, was significantly reduced 18h post-stimulation in the knockout cells. In line, the proliferation of T cells after 3 days was also impaired in the absence of P2X4 and P2X7 channels. In summary, the study demonstrates that purinergic signaling through P2X4 and P2X7 enhances initial Ca2+ events during CD8+ T cell activation and plays a crucial role in regulating downstream responses, including NFAT-1 translocation, cytokine expression, and proliferation on multiple timescales. These findings suggest that targeting purinergic signaling pathways may offer potential therapeutic interventions.

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The importance of Ca2+ microdomains for the adaptive immune response

Diercks

2024

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis

Cited by 5 publications

References 47 publications

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

2-Methoxyestradiol-3,17-O,O-bis-sulfamate (STX140) Inhibits Proliferation and Invasion via Senescence Pathway Induction in Human BRAFi-Resistant Melanoma Cells

Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation

The importance of Ca2+ microdomains for the adaptive immune response

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