In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension

Baumgart, Bethany R.; Guha, Mausumee; Hennan, James K.; Li, Julia; Woicke, Jochen; Simic, Damir; Graziano, Michael J.; Wallis, Nicola; Sanderson, Thomas P.; Bunch, Roderick T.

doi:10.1007/s00280-017-3264-2

Cited by 11 publications

(7 citation statements)

References 41 publications

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“…The extreme differences in terms of effects on pulmonary circulation between imatinib and dasatinib suggest that dasatinib-induced pulmonary vascular toxicity is molecule-related rather than class-related. On the other side, in vivo and in vitro studies aimed at evaluating the effects of dasatinib and imatinib on pulmonary vasculature demonstrated that both TKI increased levels of nitric oxide, a potent vasodilator, without inducing PAH-related adverse remodeling, thus suggesting that both the drugs could promote beneficial effects for PAH [48]. These results are in contrast with the clinical evidence of dasatinibinduced PAH.…”

Section: Mechanisms Of Pulmonary Vascular Damage Induced By Dasatinibmentioning

confidence: 93%

Pulmonary Hypertension Induced by Anticancer Drugs

Mercurio

Agnetti

Pagliaro

et al. 2018

Cardiovascular Complications in Cancer Therapy

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Section: Mechanisms Of Pulmonary Vascular Damage Induced By Dasatinibmentioning

confidence: 93%

Pulmonary Hypertension Induced by Anticancer Drugs

Mercurio

Agnetti

Pagliaro

et al. 2018

Cardiovascular Complications in Cancer Therapy

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“…Specifically, Fyn has been studied in endothelial and smooth muscle cells [27,28] while Lck is traditionally believed to exist in T-Cells and to a lesser degree NK-Cells. It is only more recently that we and other have shown Lck is expressed in PAECs and HUVECs, respectively [25,29]. It remained unknown if Lck was present at a protein or message level in the pulmonary endothelium of human lungs, or if it was altered in disease.…”

Section: Lck Is Expressed At a Mrna And Protein Level In The Endothelium Of Human Pulmonary Arteries Lck Expression In The Endothelium Comentioning

confidence: 97%

Src-Family B Kinase Inhibition Promotes Lung Endothelial Dysfunction and Guides Drug Discovery

Andruska

Ali

Tian

et al. 2021

Preprint

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Protein tyrosine kinases (PTKs) are essential for eukaryotic signaling. By targeting select PTKs, the group of drugs known as Tyrosine kinase inhibitors (TKIs) have proven to be effective for treating multiple diseases ranging from cancer to pulmonary fibrosis. However, some TKIs also paradoxically lead to the development of adverse conditions such as pulmonary arterial hypertension (PAH) by promoting endothelial cell dysfunction (ECD). We hypothesize that (1) subsets of PTKs may disproportionately modulate signaling pathways critical for endothelial homeostasis, such as BMPR2 signaling, and (2) inhibiting those pro-endothelial PTKs can promote the development of ECD. Herein we use an agnostic high-throughput siRNA screen to investigate how PTKs affect the canonical BMPR2 signaling pathway. Our major finding is that within the Src-family of non-receptor PTKs, the Src-B family promotes canonical BMPR2 signaling while the Src-A family suppresses it. We focus on two representative members of each family, Lck (for Src-B) and Fyn (for Src-A) that are the strongest activators or inhibitors of BMPR2 signaling in the screen. We confirm that Lck is expressed in the endothelium of pulmonary arteries and show that Lck knockout (termed si-Lck) in pulmonary artery endothelial cells (PAECs) suppresses canonical BMPR2 signaling while Fyn knockout (termed si-Fyn) promotes canonical BMPR2 signaling. Furthermore, Lck and Fyn are responsible for opposing functional behaviors in PAECs: si-Lck promotes apoptosis and interferes with tube formation while si-Fyn suppresses apoptosis and promotes tube formation. After analyzing the whole-transcriptome signature of si-Lck and si-Fyn PAECs we find that in addition to BMPR2 signaling suppression, si-Lck (and not si-Fyn) increases a broad number of ECD markers and increases canonical NF-κβ signaling. In summary, for the first time we show that Src-A and B Family of PTKs exert differential control over key endothelial cell signaling pathways resulting in direct phenotypic consequences. This knowledge may help to guide the design of more precise TKIs which avoid adverse drug reactions brought about through endothelial cell dysfunction.

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“…Many modifications can be induced by these two senolytic drugs of NO levels. Indeed, dasatinib can induce an increase in plasma NO in pulmonary artery and smooth muscle cells [124]. Additionally, Hu et al (2018) recently found that Src inhibition by dasatinib increases iNOS, a pro-inflammatory macrophage marker, in both intestinal and bone marrow-derived macrophages [125].…”

Section: Dasatinib/quercetinmentioning

confidence: 99%

“…Increased NO Pulmonary artery endothelial cells and smooth muscle cells [124] Increase iNOS expresion Intestinal and bone morrow-derived macrophages [125] Decrease iNOS expresion Silicotic macrophages [126] Quercetin Inhibition of iNOS [127] Inhibition of mRNA iNOS Human hepatocyte-derived cell line [128] Inhibition of NO production and iNOS expression…”

Section: Dasatinibmentioning

confidence: 99%

Senescence and Cancer: Role of Nitric Oxide (NO) in SASP

Mabrouk

Ghione

Laurens

et al. 2020

Cancers

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Cellular senescence is a cell state involved in both physiological and pathological processes such as age-related diseases and cancer. While the mechanism of senescence is now well known, its role in tumorigenesis still remains very controversial. The positive and negative effects of senescence on tumorigenesis depend largely on the diversity of the senescent phenotypes and, more precisely, on the senescence-associated secretory phenotype (SASP). In this review, we discuss the modulatory effect of nitric oxide (NO) in SASP and the possible benefits of the use of NO donors or iNOS inducers in combination with senotherapy in cancer treatment.

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In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension

Cited by 11 publications

References 41 publications

Pulmonary Hypertension Induced by Anticancer Drugs

Pulmonary Hypertension Induced by Anticancer Drugs

Src-Family B Kinase Inhibition Promotes Lung Endothelial Dysfunction and Guides Drug Discovery

Senescence and Cancer: Role of Nitric Oxide (NO) in SASP

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