Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Hayes, Candace S.; Shicora, Allyson C.; Keough, Martin P.; Snook, Adam E.; Burns, Mark R.; Gilmour, Susan K.

doi:10.1158/2326-6066.cir-13-0120-t

Cited by 130 publications

(132 citation statements)

References 44 publications

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“…The calculated lowest free binding energy of isotretinoin to Tc PAT12 substrate recognition site was -10.78 kcal.mol -1 . This value is similar to the obtained using the specific human polyamine transport blocker AMXT-1501 (-14.01 kcal.mol -1 ) [61] and lower than those of the natural substrates, putrescine (-3.31 kcal.mol -1 ) and spermidine (-3.08 kcal.mol -1 ). These data suggest that the stability of the isotretinoin—transporter complex is higher than those formed with its natural substrates probably because of the greater number of atoms (23) capable of engage in molecular interactions.…”

Section: Discussionsupporting

confidence: 86%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

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Section: Discussionsupporting

confidence: 86%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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“…Indeed, polyamines (via the arginine-ornithine-polyamine axis) contribute to a tumor-permissive microenvironment through myriad effects on immunosurveillance mechanisms (57)(58)(59), so efforts to study polyamine depletion in this context are warranted. Indeed, COX activity in tumors contributes to immune evasion and biochemical inhibition of these pathways restores antitumor immunity (60), providing an additional potential mechanism for the enhanced antitumor activities seen with DFMO and celecoxib in our models.…”

Section: Discussionmentioning

confidence: 99%

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression

Evageliou

Haber

et al. 2016

Clinical Cancer Research

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Purpose: Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC. Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.Experimental Design: We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists. We investigated difluoromethylornithine (DFMO; an inhibitor of Odc, the rate-limiting enzyme in polyamine synthesis), SAM486 (an inhibitor of Amd1, the second ratelimiting enzyme), and celecoxib (an inducer of Sat1 and polyamine catabolism) in both the preemptive setting and in the treatment of established tumors. In vitro assays were performed to identify mechanisms of activity.Results: An optimized polyamine antagonist regimen using DFMO and SAM486 to inhibit both rate-limiting enzymes in polyamine synthesis potently blocked neuroblastoma initiation in transgenic mice, underscoring the requirement for polyamines in MYC-driven oncogenesis. Furthermore, the combination of DFMO with celecoxib was found to be highly active, alone, and combined with numerous chemotherapy regimens, in regressing established tumors in both models, including tumors harboring highest risk genetic lesions such as MYCN amplification, ALK mutation, and TP53 mutation with multidrug resistance.Conclusions: Given the broad preclinical activity demonstrated by polyamine antagonist regimens across diverse in vivo models, clinical investigation of such approaches in neuroblastoma and potentially other MYC-driven tumors is warranted.

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“…This connection is not only involved in T cell anergy but also in the generation of myeloid-derived suppressor cells (MDSC), as indicated by earlier studies [46, 47]. Further, recent work clearly connects IDO1, arginase and polyamines in MDSC accumulation and function [48, 49]. In summary, IDO1 is the focus of numerous major pro-inflammatory pathways in cancer where it acts as a pivotal modifier of disease progression.…”

Section: Ido1 Modifies Inflammation and Immunitymentioning

confidence: 79%

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

Prendergast¹,

Mondal²,

Dey³

et al. 2018

Trends in Cancer

142

116

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We discuss how small molecule inhibitors of the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDOi) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO activation in cancer supports inflammatory processes that IDOi can re-program to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes TDO and IDO2 may also safely broaden efficacy. Understanding IDOi as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting its collateral damage.

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Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

Cited by 130 publications

References 44 publications

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

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