IRL‐1620, a tumor selective vasodilator, augments the uptake and efficacy of chemotherapeutic agents in prostate tumor rats

Rajeshkumar, N.V.; Matwyshyn, George A.; Gulati, Anil

doi:10.1002/pros.20556

Cited by 13 publications

(11 citation statements)

References 61 publications

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“…However, major efforts were done in the field of ET-1 receptor antagonists. Driven by positive preclinical results, different clinical trials were initiated, reaching phases II to III with selective or specific ET A R antagonists or with the dual ET A R and ET B R antagonist or by the selective ET B R agonist IRL-1620, which may be used for drug delivery, by increasing tumor perfusion to potentiate the therapeutic efficacy of anticancer agents and of radiation therapy (21,24).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ␤-arrestin 1 (␤-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ET AR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ␤-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.␤-arrestin; cancer; endothelin-1; endothelin-1 receptor; target therapy RECENT INVESTIGATIONS have consistently suggested that endothelin-1 (ET-1), a small bioactive peptide of 21 residues derived from longer prepro-ET-1 precursor, is an important signal messenger in different pathological conditions, including human cancers (24,35). ET-1 belongs to a family of closely related peptides that include ET-2 and ET-3, which are all similar in structure to ET-1, but are separate gene products, with tissue-specific expression. ETs act mainly via G protein-coupled receptors (GPCR) from endothelin receptor type A (ET A R) and B (ET B R) (24). The two receptors can be differentiated by agonists and antagonists binding affinity and in their cellular distributions. The ET A R binds ET-1 with the greatest affinity, whereas ET-1, ET-2, and ET-3 all have equal affinity for the ET B R.It is now well known that ET-1 receptors can activate several signaling pathways in a G protein-independent manner via complexes with ␤-arrestin (␤-arr)-1 or -2 (18, 24). The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig. 1A). A lesson learned from various tumor models is that there are different expression profiles of the ET-1 receptors compared with normal tissues. There are cancers expres...

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Section: Therapeutic Approachesmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…There are a number of ET B agonists available for study including the endogenous peptide ET-3 and related sarafotoxin 6c (S6c) in addition to peptide agonists such as BQ3020 and IRL 1620. IRL-1620 is of particular significance as it is under investigation in a number of therapeutic areas with efficacy demonstrated in animal models of stroke [12] and as an adjunct for improved delivery of chemotherapy targeting solid tumours [13]. It would therefore be of interest to determine the relative effect of these agonists in a number of disease relevant pathways, with comparison to ET-3 responses to determine evidence of bias.…”

Section: Ligand Bias At the Etb Receptormentioning

confidence: 99%

Evidence for biased agonists and antagonists at the endothelin receptors

Maguire

2016

Life Sciences

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Biased ligands represent a new strategy for the development of more effective and better tolerated drugs. To date there has been a paucity of research exploring the potential of ligands that exhibit either G protein or β-arrestin pathway selectivity at the endothelin receptors. Re-analysis of data may allow researchers to determine whether there is existing evidence that the endogenous ET peptides or currently available agonists and antagonists exhibit pathway bias in a particular physiological or disease setting and this is explored in the review. An alternative to molecules that bind at the orthosteric site of the ET receptors are cell penetrating peptides that interact with a segment of an intracellular loop of the receptor to modify signalling behaviour. One such peptide IC2B has been shown to have efficacy in a model of pulmonary arterial hypertension. Finally, understanding the molecular pathways that contribute to disease is critical to determining whether biased ligands will provide clinical benefit. The role of ETA signalling in ovarian cancer has been delineated in some detail and this has led to the suggestion that the development of ETA G protein biased agonists or β-arrestin biased antagonists should be explored.

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“…This resulted in the enhancement of the tumor accumulation of small anti-cancer drugs and tumor regression. 15,16) Based on these reports, a phase II clinical trial in which co-administration of IRL-1620 and a small molecule anti-cancer drug was performed in patients with biliary tract cancer was reported. 17) Unfortunately, the trial failed to meet the predetermined endpoint.…”

Section: Introductionmentioning

confidence: 99%

Effect of an Endothelin B Receptor Agonist on the Tumor Accumulation of Nanocarriers

Feng

Nam

Yoshikawa

et al. 2020

Biological & Pharmaceutical Bulletin

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Enhancing blood flow to tumors is a prominent strategy for improving the tumor accumulation of macromolecular drugs through the enhanced permeability and retention (EPR) effect. IRL-1620 is an agonist of the endothelin B receptor, and is a promising molecule to enhance tumor blood flow by activating endothelial nitric oxide synthase. However, contradictory effects on tumor blood flow modulation have been reported because the effects of IRL-1620 may differ in different animal models. Here, we examined for the first time the effect of IRL-1620 on the EPR effect for PEGylated liposomes in a CT-26 murine colon cancer model. Co-injection of IRL-1620 at an optimum dose (3 nmol/kg) nearly doubled the tumor accumulation of liposomes compared with controls, indicating that IRL-1620 enhanced the EPR effect in the present colon cancer model. Co-injection of IRL-1620 is a promising strategy to improve the therapeutic effects of macromolecular drugs while reducing their side effects.

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IRL‐1620, a tumor selective vasodilator, augments the uptake and efficacy of chemotherapeutic agents in prostate tumor rats

Abstract: IRL-1620 significantly enhanced the uptake and efficacy of anticancer agents in prostate cancer.

Cited by 13 publications

References 61 publications

Endothelin therapeutics in cancer: Where are we?

Endothelin therapeutics in cancer: Where are we?

Evidence for biased agonists and antagonists at the endothelin receptors

Effect of an Endothelin B Receptor Agonist on the Tumor Accumulation of Nanocarriers

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