Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects. iScience 2021 Jun 25;24(6):102673
Date
07/01/2021Pubmed ID
34189437Pubmed Central ID
PMC8215227DOI
10.1016/j.isci.2021.102673Scopus ID
2-s2.0-85107809306 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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 TÂ cell response, implicating their potential antitumor immunomodulatory mechanism.
Author List
Cheng G, Hardy M, Topchyan P, Zander R, Volberding P, Cui W, Kalyanaraman BAuthors
Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMicael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
