title: A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity.
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 significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O2-dependent activation of HIFα using polyamides.
  
  
  CONCLUSIONS
  Py-Im polyamides target and disrupt the adaptive hypoxic responses in multiple myeloma cells that may have clinical significance as a therapeutic strategy to treat myeloma engrafted in the bone marrow microenvironment.
authors.affiliation: Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California. University of California, Los Angeles, Los Angeles, California.
authors.forename: Veena S
authors.initials: VS
authors.lastname: Mysore
authors.affiliation: Division of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, California.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Szablowski
authors.affiliation: Division of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, California.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
authors.affiliation: Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California. University of California, Los Angeles, Los Angeles, California. pfrost@ucla.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Frost
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D001393:Azoles / Q000008:administration & dosage* / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009757:Nylons / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009757:Nylons; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human