Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects
Summary: 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 reductas...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221006416 |
| _version_ | 1818612560894623744 |
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| author | Gang Cheng Micael Hardy Paytsar Topchyan Ryan Zander Peter Volberding Weiguo Cui Balaraman Kalyanaraman |
| author_facet | Gang Cheng Micael Hardy Paytsar Topchyan Ryan Zander Peter Volberding Weiguo Cui Balaraman Kalyanaraman |
| author_sort | Gang Cheng |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-16T15:48:10Z |
| format | Article |
| id | doaj.art-bd646fa91a0e4e0490894678bf35d011 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-16T15:48:10Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-bd646fa91a0e4e0490894678bf35d0112022-12-21T22:25:45ZengElsevieriScience2589-00422021-06-01246102673Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effectsGang Cheng0Micael Hardy1Paytsar Topchyan2Ryan Zander3Peter Volberding4Weiguo Cui5Balaraman Kalyanaraman6Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USAAix Marseille Univ, CNRS, ICR, UMR 7273, Marseille 13013, FranceMicrobiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Versiti Blood Research Institute, 8733 Watertown Plank Road, Milwaukee, WI 53226, USAMicrobiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Versiti Blood Research Institute, 8733 Watertown Plank Road, Milwaukee, WI 53226, USAMicrobiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Versiti Blood Research Institute, 8733 Watertown Plank Road, Milwaukee, WI 53226, USAMicrobiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Versiti Blood Research Institute, 8733 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Center for Disease Prevention Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004221006416DrugsOrganic chemistryBiological sciencesImmunology |
| spellingShingle | Gang Cheng Micael Hardy Paytsar Topchyan Ryan Zander Peter Volberding Weiguo Cui Balaraman Kalyanaraman Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects iScience Drugs Organic chemistry Biological sciences Immunology |
| title | Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects |
| title_full | Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects |
| title_fullStr | Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects |
| title_full_unstemmed | Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects |
| title_short | Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects |
| title_sort | mitochondria targeted hydroxyurea inhibits oxphos and induces antiproliferative and immunomodulatory effects |
| topic | Drugs Organic chemistry Biological sciences Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221006416 |
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