{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:54:04Z","timestamp":1779886444766,"version":"3.53.1"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009841","name":"University of the Pacific","doi-asserted-by":"publisher","award":["Faculty SEED grant"],"award-info":[{"award-number":["Faculty SEED grant"]}],"id":[{"id":"10.13039\/100009841","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>A hallmark of cancer is the dysregulation of the cell cycle. The CDK4\/6 inhibitor palbociclib is approved for treating advanced estrogen-receptor-positive breast cancer, but its success is limited by the development of acquired resistance owing to long-term therapy despite promising clinical outcomes. This situation necessitates the development of potential combination strategies. Here, we report that didox, an inhibitor of ribonucleotide reductase in combination with palbociclib, can overcome palbociclib resistance in ER-positive and ER-negative breast cancers. This study shows didox downregulates an element of the cell cycle checkpoint, cyclin D1, accompanied by a reduction in NF-\u03baB activity in vitro and tumor growth inhibition of palbociclib-resistant ER positive breast cancer tumor growth in vivo. Furthermore, didox induces cell cycle arrest at G1 as well as reduces ROS generated by on-target effects of palbociclib on the cell cycle. Our current study also reports that the CCND1 and RRM2 upregulation associated with palbociclib-resistant breast cancers decreases upon ribonucleotide reductase inhibition. Our data present a novel and promising biomarker-driven combination therapeutic approach for the treatment of ER-positive and ER-negative breast cancers that involves the inhibition of the CDK4\/6-cyclinD1\/pRb cell cycle axis that merits further clinical investigation in human models.<\/jats:p>","DOI":"10.3390\/cancers16050975","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T07:56:02Z","timestamp":1709106962000},"page":"975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting the Cell Cycle, RRM2 and NF-\u03baB for the Treatment of Breast Cancers"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9592-0114","authenticated-orcid":false,"given":"Nahid","family":"Sultana","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard L.","family":"Elford","sequence":"additional","affiliation":[{"name":"Molecules for Health, Inc., Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0120-879X","authenticated-orcid":false,"given":"Jesika S.","family":"Faridi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1158\/0008-5472.CAN-21-3062","article-title":"CDK4\/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade","volume":"82","author":"Tong","year":"2022","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1158\/1535-7163.MCT-21-0411","article-title":"Cyclin-dependent Kinase 4\/6 Inhibitor Palbociclib in Combination with Ralaniten Analogs for the Treatment of Androgen Receptor\u2013positive Prostate and Breast Cancers","volume":"21","author":"Tien","year":"2022","journal-title":"Mol. 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