Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers
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 outcome...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/16/5/975 |
| _version_ | 1797264747102470144 |
|---|---|
| author | Nahid Sultana Howard L. Elford Jesika S. Faridi |
| author_facet | Nahid Sultana Howard L. Elford Jesika S. Faridi |
| author_sort | Nahid Sultana |
| collection | DOAJ |
| description | 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-κB 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. |
| first_indexed | 2024-04-25T00:33:49Z |
| format | Article |
| id | doaj.art-d91173e907cc498b8fef3ce40bb01bec |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-04-25T00:33:49Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d91173e907cc498b8fef3ce40bb01bec2024-03-12T16:41:03ZengMDPI AGCancers2072-66942024-02-0116597510.3390/cancers16050975Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast CancersNahid Sultana0Howard L. Elford1Jesika S. Faridi2Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USAMolecules for Health, Inc., Richmond, VA 23219, USADepartment of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USAA 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-κB 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.https://www.mdpi.com/2072-6694/16/5/975palbociclibRRM2NF-κBcell cycle |
| spellingShingle | Nahid Sultana Howard L. Elford Jesika S. Faridi Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers Cancers palbociclib RRM2 NF-κB cell cycle |
| title | Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers |
| title_full | Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers |
| title_fullStr | Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers |
| title_full_unstemmed | Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers |
| title_short | Targeting the Cell Cycle, RRM2 and NF-κB for the Treatment of Breast Cancers |
| title_sort | targeting the cell cycle rrm2 and nf κb for the treatment of breast cancers |
| topic | palbociclib RRM2 NF-κB cell cycle |
| url | https://www.mdpi.com/2072-6694/16/5/975 |
| work_keys_str_mv | AT nahidsultana targetingthecellcyclerrm2andnfkbforthetreatmentofbreastcancers AT howardlelford targetingthecellcyclerrm2andnfkbforthetreatmentofbreastcancers AT jesikasfaridi targetingthecellcyclerrm2andnfkbforthetreatmentofbreastcancers |