Telmisartan-Induced Cytotoxicity &lt;i&gt;via&lt;/i&gt; G&lt;sub&gt;2&lt;/sub&gt;/M Phase Arrest in Renal Cell Carcinoma Cell Lines

Tsujiya, Yoshie; Hasegawa, Akira; Yamamori, Motohiro; Okamura, Noboru

doi:10.1248/bpb.b21-00654

Cited by 4 publications

(3 citation statements)

References 41 publications

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“… 62 , 63 Studies in the literature have revealed that Tel could arrest the cell cycle of renal cell carcinoma cells to the G2/M phase. 45 To further explore whether ECM/Tel could arrest the cell cycle of 4T1 cells to G2/M to promote radiosensitization, the cell cycle of 4T1 cells treated with Tel or ECM/Tel was determined by flow cytometry. The results ( Figure 5A and B ) showed that after being treated with Tel, the S phase of 4T1 cells decreased from 36.6% to 27.3%, and the G2/M phase increased from 8.7% to 15.7%.…”

Section: Resultsmentioning

confidence: 99%

“… 43 , 44 Notably, recent studies also suggest that Tel can inhibit the proliferation of different tumor cells by inducing cell cycle arrest to the G2/M phase. 45 , 46 For radiotherapy, studies have shown that the G2/M phase is the most radiosensitive phase for tumor cells. 47 G2/M cell cycle arrest of tumor cells can increase the radiosensitivity of tumor cells and promote radiosensitization.…”

Section: Introductionmentioning

confidence: 99%

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Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model

Chen,

Wang,

Meng

et al. 2024

IJN

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Background Radiation stimulates the secretion of tumor stroma and induces resistance, recurrence, and metastasis of stromal-vascular tumors during radiotherapy. The proliferation and activation of tumor-associated fibroblasts (TAFs) are important reasons for the production of tumor stroma. Telmisartan (Tel) can inhibit the proliferation and activation of TAFs (resting TAFs), which may promote radiosensitization. However, Tel has a poor water solubility. Methods In this study, self-assembled telmisartan nanoparticles (Tel NPs) were prepared by aqueous solvent diffusion method to solve the insoluble problem of Tel and achieve high drug loading of Tel. Then, erythrocyte membrane (ECM) obtained by hypotonic lysis was coated on the surface of Tel NPs (ECM/Tel) for the achievement of in vivo long circulation and tumor targeting. Immunofluorescence staining, western blot and other biological techniques were used to investigate the effect of ECM/Tel on TAFs activation inhibition (resting effect) and mechanisms involved. The multicellular spheroids (MCSs) model and mouse breast cancer cells (4T1) were constructed to investigate the effect of ECM/Tel on reducing stroma secretion, alleviating hypoxia, and the corresponding promoting radiosensitization effect in vitro. A mouse orthotopic 4T1 breast cancer model was constructed to investigate the radiosensitizing effect of ECM/Tel on inhibiting breast cancer growth and lung metastasis of breast cancer. Results ECM/Tel showed good physiological stability and tumor-targeting ability. ECM/Tel could rest TAFs and reduce stroma secretion, alleviate hypoxia, and enhance penetration in tumor microenvironment. In addition, ECM/Tel arrested the cell cycle of 4T1 cells to the radiosensitive G2/M phase. In mouse orthotopic 4T1 breast cancer model, ECM/Tel played a superior role in radiosensitization and significantly inhibited lung metastasis of breast cancer. Conclusion ECM/Tel showed synergistical radiosensitization effect on both the tumor microenvironment and tumor cells, which is a promising radiosensitizer in the radiotherapy of stroma-vascular tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model

Chen,

Wang,

Meng

et al. 2024

IJN

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“…None of the other ARBs showed a similar toxicity at 100 µM (Figure 7A,C), illustrating the unique action of telmisartan on microglia. Telmisartan can induce apoptosis in a variety of cell types, although these are mainly transformed cells, so this activity is considered beneficial anti-tumor activity [55,[97][98][99]]. Telmisartan's toxicity was partially ameliorated by 3-methyladenine, an inhibitor of early autophagy (Figure 8A), and prevented by pretreatment with the pan-caspase inhibitor Z-VAD-FMK (Figure 8B).…”

Section: Discussionmentioning

confidence: 99%

Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia

Affram,

Janatpour,

Shanbhag

et al. 2024

Neuroglia

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Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting microglial activation could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects in the brain and are considered potential therapies for neurodegenerative diseases and neurotrauma. Although all ARBs are angiotensin II receptor type I antagonists, some ARBs act through other signaling pathways, allowing for multiple mechanisms of action. The anti-inflammatory mechanisms of ARBs are not well understood. Methods: In this study, we compared eight different FDA-approved ARBs for their ability to reduce the LPS stimulation of primary microglia or BV2 cells through analyses of nitric oxide production, reactive oxygen species generation, and the mRNA of proinflammatory cytokines. Finding specific and unique effects of telmisartan, we interrogated signaling pathways and other downstream effectors of telmisartan activity on microglia. Results: Our findings indicate that telmisartan showed the greatest efficacy in reducing the LPS induction of reactive oxygen species (ROS) and nitric oxide production in microglia. Uniquely amongst ARBs, telmisartan activated AMPK phosphorylation and inhibited mTOR phosphorylation. Telmisartan’s anti-inflammatory activity was partially inhibited by the AMPK inhibitor compound C. Furthermore, telmisartan uniquely induced markers of autophagy in microglia through an AMPK–mTOR–autophagy pathway. Telmisartan also reduced microglial viability. Telmisartan’s cytotoxicity was partially ameliorated by an autophagy inhibitor and a pan-caspase inhibitor, indicating a link between microglial autophagy and apoptosis. Conclusions: We conclude that telmisartan has unique properties relative to other ARBs, including potent anti-inflammatory actions and an induction of microglial autophagy, which may enable specific therapeutic uses.

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Interaction of telmisartan and related sartans with the programmed cell death-ligand 1 (PD-L1) protein dimer: a molecular docking analysis

Vergoten,

Bailly

2023

Futur J Pharm Sci

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BackgroundTelmisartan (TLT) is a prototypic angiotensin receptor blocker largely used to treat hypertension worldwide. In addition to its cardioprotective effects, TLT presents pleiotropic activities and notably displays noticeable anti-inflammatory and antitumor effects. The repression of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint may be implicated antitumor action of TLT, as it is the case with many other compounds equipped with a biphenyl moiety. We have used molecular modeling to compare the interaction of TLT and derivatives with the PD-L1 dimer protein.ResultsTwo molecules, TLT-dimer and TLT-acylglucuronide, were found to form more stable complexes with PD-L1 than TLT itself. In parallel, the docking analysis performed with a series of 12 sartans led to the identification of Olmesartan as a potential PD-L1 binder. The stacked biphenyl unit of Olmesartan positions the molecule along the groove delimited by the two protein monomers. The flanking tetrazole and imidazole moieties, on each side of the biphenyl unit of Olmesartan, contribute favorably to the protein interaction via specific hydrogen bonding interactions.ConclusionsThe computational analysis suggests a possible binding of Olmesartan to PD-L1 dimer and thus offers novel perspectives for the design of small molecules capable of interrupting the PD-1/PD-L1 immune checkpoint. Experimental studies are warranted to validate the hypothesis.Graphical abstract

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Telmisartan-Induced Cytotoxicity <i>via</i> G<sub>2</sub>/M Phase Arrest in Renal Cell Carcinoma Cell Lines

Cited by 4 publications

References 41 publications

Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model

Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model

Telmisartan Reduces LPS-Mediated Inflammation and Induces Autophagy of Microglia

Interaction of telmisartan and related sartans with the programmed cell death-ligand 1 (PD-L1) protein dimer: a molecular docking analysis

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