Journal article
Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects
iScience, Vol.24(6), pp.102673-102673
06/25/2021
DOI: 10.1016/j.isci.2021.102673
PMCID: PMC8215227
PMID: 34189437
Abstract
Hydroxyurea (HU), an FDA-approved drug for treating sickle cell disease, is used as an antitumor drug alone and together with conventional chemotherapeutics or radiation therapy. HU is used primarily to treat myeloproliferative diseases because it inhibits the enzyme ribonucleotide reductase involved in DNA synthesis. The hydroxyl group in HU is considered critical for its antiproliferative and chemotherapeutic effects. Here, we substituted the hydroxyl group in HU with a triphenylphosphonium cation attached to an alkyl group with different chain lengths, forming a new class of mitochondria-targeted HU (Mito-HU). Elongating the alkyl side chain length increased the hydrophobicity of Mito-HUs, inhibition of oxidative phosphorylation, and antiproliferative effects in tumor cells. Both mitochondrial complex I- and complex III-induced oxygen consumption decreased with the increasing hydrophobicity of Mito-HUs. The more hydrophobic Mito-HUs also potently inhibited the monocytic myeloid-derived suppressor cells and suppressive neutrophils, and stimulated T cell response, implicating their potential antitumor immunomodulatory mechanism.
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•Mito-HUs target OXPHOS & inhibit cancer cell proliferation at sub-micromolar levels•More hydrophobic Mito-HUs more potently inhibit mitochondrial respiration•More hydrophobic Mito-HUs may inhibit MDSCs & neutrophils, activate T cells•The IC50s for inhibition are similar in tumor cells, MDSCs, and neutrophils
Drugs; Organic chemistry; Biological sciences; Immunology
Details
- Title: Subtitle
- Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects
- Creators
- Gang Cheng - Medical College of WisconsinMicael Hardy - Aix-Marseille UniversitéPaytsar Topchyan - Medical College of WisconsinRyan Zander - Medical College of WisconsinPeter Volberding - Medical College of WisconsinWeiguo Cui - Medical College of WisconsinBalaraman Kalyanaraman - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.24(6), pp.102673-102673
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.isci.2021.102673
- PMID
- 34189437
- PMCID
- PMC8215227
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Language
- English
- Date published
- 06/25/2021
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297329302771
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