A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity
Veena S Mysore1, Jerzy Szablowski2, Peter B Dervan2
1Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California. University of California, Los Angeles, Los Angeles, California.
Unlabelled:
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.
Implications:
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.
Insights
This study shows that a novel pyrrole-imidazole polyamide (HIF-PA) can overcome chemotherapy resistance in multiple myeloma by targeting hypoxia-inducible factors (HIF). This therapeutic strategy shows promise for treating bone marrow microenvironment cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Multiple myeloma is an incurable blood cancer known for developing resistance to chemotherapy.
- Hypoxic bone marrow conditions are linked to multiple myeloma progression, angiogenesis, and treatment resistance.
- Hypoxia-inducible factors (HIFs) mediate adaptive cellular responses to hypoxia, offering potential therapeutic targets in malignancies.
Purpose of the Study:
- To investigate the oxygen-dependent expression of HIF1α and HIF2α in multiple myeloma cells.
- To evaluate the anti-multiple myeloma effects of a novel pyrrole-imidazole (Py-Im) polyamide (HIF-PA) that disrupts HIF DNA binding.
- To assess the therapeutic potential of HIF-PA in preclinical models of multiple myeloma.
Main Methods:
- Assessed oxygen-dependent HIF1α and HIF2α expression in myeloma cell lines.
- Investigated the mechanism of action of HIF-PA, a sequence-specific DNA-binding polyamide.
- Evaluated HIF-PA efficacy in vitro using myeloma cells resistant to hypoxia-mediated apoptosis.
- Utilized xenograft models to assess HIF-PA's impact on tumor volume and cell engraftment in the bone marrow.
Main Results:
- HIF1α expression was oxygen-dependent in most tested myeloma cell lines, unlike HIF2α.
- HIF-PA demonstrated cell permeability, nuclear localization, and specific DNA binding, comparable to HIFs.
- HIF-PA treatment successfully overcame hypoxia-induced resistance to apoptosis in multiple myeloma cells in vitro.
- In vivo studies showed HIF-PA significantly reduced tumor volume and increased hypoxic and apoptotic regions in solid tumors and bone marrow engraftments.
Conclusions:
- Py-Im polyamides effectively target and disrupt adaptive hypoxic responses in multiple myeloma cells.
- This targeted disruption of hypoxic pathways presents a potential therapeutic strategy for treating bone marrow microenvironment multiple myeloma.
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