A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

Molecular Cancer Research : MCR
Veena S MysorePatrick J Frost

Abstract

Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained by the differential expression of the regulatory prolyl hydroxylase isoforms. The anti-multiple myeloma effects of a sequence-specific DNA-binding pyrrole-imidazole (Py-Im) polyamide (HIF-PA), which disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable with that of HIFs. Most of the multiple myeloma cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA signif...Continue Reading

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Citations

Jan 10, 2019·Annual Review of Pharmacology and Toxicology·Gregg L Semenza
Jun 21, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mélanie LambertMarie-Hélène David-Cordonnier
Aug 10, 2019·Molecular Cancer Therapeutics·Mario I VegaAlan Lichtenstein
Feb 12, 2019·Advanced Drug Delivery Reviews·Zutao YuHiroshi Sugiyama

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