Emerging Applications of Argatroban in the Management of Systemic Malignancies

Kapoor, Shailendra

doi:10.1161/circresaha.112.300745

Cited by 1 publication

(1 citation statement)

References 9 publications

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“…The compound is currently prescribed against heparin-induced thrombocytopenia and for use in patients undergoing percutaneous coronary intervention 68. Argatroban's antimetastatic potential has been recognized earlier 53-55; however, in lack of previous insights on the underlying molecular mechanism, it was hypothesized that this effect is mediated via its well-known mechanism of action as a competitive inhibitor of thrombin 69. Here, we demonstrate that the metastasis-inhibitory property of argatroban relies on a distinct mechanism of action that involves disruption of the interaction of E2F1 with its newly identified coactivator MTA1, eventually leading to downregulation of metastatic targets.…”

Section: Discussionmentioning

confidence: 99%

Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic Cancers

Goody¹,

Gupta²,

Engelmann³

et al. 2019

Theranostics

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Metastasis management remains a long-standing challenge. High abundance of E2F1 triggers tumor progression by developing protein-protein interactions (PPI) with coregulators that enhance its potential to activate a network of prometastatic transcriptional targets. Methods: To identify E2F1-coregulators, we integrated high-throughput Co-immunoprecipitation (IP)/mass spectometry, GST-pull-down assays, and structure modeling. Potential inhibitors of PPI discovered were found by bioinformatics-based pharmacophore modeling, and transcriptome profiling was conducted to screen for coregulated downstream targets. Expression and target gene regulation was validated using qRT-PCR, immunoblotting, chromatin IP, and luciferase assays. Finally, the impact of the E2F1-coregulator complex and its inhibiting drug on metastasis was investigated in vitro in different cancer entities and two mouse metastasis models. Results: We unveiled that E2F1 forms coactivator complexes with metastasis-associated protein 1 (MTA1) which, in turn, is directly upregulated by E2F1. The E2F1:MTA1 complex potentiates hyaluronan synthase 2 (HAS2) expression, increases hyaluronan production and promotes cell motility. Disruption of this prometastatic E2F1:MTA1 interaction reduces hyaluronan synthesis and infiltration of tumor-associated macrophages in the tumor microenvironment, thereby suppressing metastasis. We further demonstrate that E2F1:MTA1 assembly is abrogated by small-molecule, FDA-approved drugs. Treatment of E2F1/MTA1-positive, highly aggressive, circulating melanoma cells and orthotopic pancreatic tumors with argatroban prevents metastasis and cancer relapses in vivo through perturbation of the E2F1:MTA1/HAS2 axis. Conclusion: Our results propose argatroban as an innovative, E2F-coregulator-based, antimetastatic drug. Cancer patients with the infaust E2F1/MTA1/HAS2 signature will likely benefit from drug repositioning.

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