Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation

Kazemi, Zahra; Bergmayr, Christian; Prchal-Murphy, Michaela; Javaheri, Tahereh; Themanns, Madeleine; Phạm, Hà; Strohmaier, Wolfgang; Sexl, Veronika; Freissmuth, Michael; Zebedin-Brandl, Eva

doi:10.1124/mol.116.103267

Cited by 8 publications

(30 citation statements)

References 39 publications

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“…CXCR4 is a chemokine receptor whose expression has been shown to increase in response to treprostinil exposure in hematopoietic stem cells (24). CXCR4 message increased slightly, but insignificantly, in uninvolved tissue from treprostinil-treated, naïve mice and urethane-treated mice.…”

Section: Resultsmentioning

confidence: 99%

“…Elevated CXCR4 expression correlates with aggressive metastasis, advanced stage disease, and shorter overall NSCLC survival rates(35). A recent publication by Kazemi and colleagues demonstrated that treprostinil (and not iloprost or beraprost) increased CXCR4 expression in hematopoetic stem and progenitor cells (HSPC), enhanced CXCR4 mediated HSPC migration, and improved the engraftment of HSPCs in lethally irradiated mice without impairing their self-renewal capacity(24). The enhanced ability of treprostinil to boost CXCR4 related pathway activity may explain its lack of chemopreventive properties.…”

Section: Discussionmentioning

confidence: 99%

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The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

Dwyer‐Nield

Hickey

Friedman³

et al. 2017

Cancer Prevention Research

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Prostacyclin (prostaglandin I2, PGI2) over-production in FVB/N mice prevents the formation of carcinogen and tobacco smoke induced adenomas, and administration of the oral prostacyclin analog iloprost to wild type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared to placebo. Next generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). Based on our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the maximum tolerated dose in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer, however we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost’s chemopreventive mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

Dwyer‐Nield

Hickey

Friedman³

et al. 2017

Cancer Prevention Research

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“…In fact, this dose provided the optimum beneficial effect in promoting hematopoietic stem cell transplantation in lethally irradiated recipient mice [24]. In previous work, we noted a bell-shaped dose-response curve of treprostinil, suggesting that a higher dose of treprostinil is less beneficial than the currently used dose.…”

Section: Discussionmentioning

confidence: 97%

Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

et al. 2018

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Sinusoidal obstruction syndrome (SOS) is a major complication after hematopoietic stem cell transplantation and belongs to a group of diseases increasingly identified as transplant-related systemic endothelial disease. Administration of defibrotide affords some protection against SOS, but the effect is modest. Hence, there is unmet medical need justifying the preclinical search for alternative approaches. Prostaglandins exert protective actions on endothelial cells of various vascular beds. Here, we explored the therapeutic potential of the prostacyclin analog treprostinil to prevent SOS. Treprostinil acts via stimulation of IP, EP2, and EP4 receptors, which we detected in murine liver sinusoidal endothelial cells (LSECs). Busulfan-induced cell death was reduced when pretreated with treprostinil in vitro. In a murine in vivo model of SOS, concomitantly administered treprostinil caused lower liver weight-to-body weight ratios indicating liver protection. Histopathological changes were scored to assess damage to liver sinusoidal endothelial cells, to hepatocytes, and to the incipient fibrotic reaction. Treprostinil indeed reduced sinusoidal endothelial cell injury, but this did not translate into reduced liver cell necrosis or fibrosis. In summary, our observations provide evidence for a beneficial effect of treprostinil on damage to LSECs but unexpectedly treprostinil was revealed as a double-edged sword in SOS.Key messages Murine liver sinusoidal endothelial cells (LSECs) express prostanoid receptors.Treprostinil reduces busulfan-induced cell death in vitro.Treprostinil lowers liver weight-to-body weight ratios in mice.Treprostinil positively affects LSECs in mice but not hepatic necrosis/fibrosis.

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“…Raising cAMP by activation of Gαs enhances engraftment of HSCs [4]. This can be achieved by pretreating HSCs in vitro with prostanoid E and I receptor agonists, e.g., dimethyl-PGE2 (dmPGE2) [5,6] or treprostinil [7]. Treprostinil has two advantages: it is an approved drug and it can also be administered in vivo, which further enhances bone marrow reconstitution in recipient animals [7].…”

Section: Introductionmentioning

confidence: 99%

“…This can be achieved by pretreating HSCs in vitro with prostanoid E and I receptor agonists, e.g., dimethyl-PGE2 (dmPGE2) [5,6] or treprostinil [7]. Treprostinil has two advantages: it is an approved drug and it can also be administered in vivo, which further enhances bone marrow reconstitution in recipient animals [7]. Similarly, genetic deletion or inhibition of dipeptidyl peptidase-4 (DPP4/CD26) promotes the reconstitution of the bone marrow after HCT [8,9].…”

Section: Introductionmentioning

confidence: 99%

Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation

et al. 2019

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The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. Key messages & Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. & Vildagliptin enhances in vitro migration of pretreated HSPCs. & Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. & Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.

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Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation

Cited by 8 publications

References 39 publications

The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation

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