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Peer-reviewedCC BY-NC-NDCancer science

CDK4/6 Inhibitors and Curcumin Synergistically Suppress HER2- Breast Cancer via Lethal ROS and Inhibition of Metastasis.

  • Chenyu Wang1
  • Yiqin Zou1
  • Chunyu Chang1
  • Siyue Liu1
  • Xiankun Ke1
  • Liang Hu1
  • Di Wang1
  • Yukang Lu1
  • Shiwen Luo1
  • Sijian Huang1
  • Yilan Hu1,2
  • Wenqi Yu1
3 more authors
  • Aiping Deng3
  • Ming Yue3
  • Jue Jiang1,4
4 affiliations
  1. 1School of Medicine, Institute of Infection, Immunology and Tumor Microenvironment, Wuhan University of Science and Technology, Wuhan, China.
  2. 2Wuhan University of Science and Technology Affiliated Wuchang Hospital, Wuhan, China.
  3. 3Department of Pharmacy, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  4. 4Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan, China.
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Abstract

CDK4/6 inhibitors represent a key therapy for HR+/HER2- breast cancer, yet resistance and limited efficacy in triple-negative breast cancer (TNBC) remain significant challenges. Using a self-established drug combination prediction platform, we identified a strong synergy between the CDK4/6 inhibitor palbociclib and the natural compound curcumin across both HR+/HER2- and TNBC models, an effect that was also observed with ribociclib. Mechanistically, the combination led to a collapse of redox homeostasis. Despite upregulating transcriptional antioxidant responses, the treatment downregulated critical ROS-detoxifying enzymes (e.g., GPX4) and depleted glutathione. This imbalance induced lethal oxidative stress, lipid peroxidation, and extensive DNA damage. Furthermore, excessive ROS accumulation contributed to suppression of epithelial-mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N-acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox-based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+/HER2- breast cancer and TNBC.

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Cite

BibTeXRIS
BibTeX
@article{wang2026cdk46,
  title = {{CDK4/6 Inhibitors and Curcumin Synergistically Suppress HER2- Breast Cancer via Lethal ROS and Inhibition of Metastasis.}},
  author = {Chenyu Wang and Yiqin Zou and Chunyu Chang and Siyue Liu and Xiankun Ke and Liang Hu and Di Wang and Yukang Lu and Shiwen Luo and Sijian Huang and Yilan Hu and Wenqi Yu and Aiping Deng and Ming Yue and Jue Jiang},
  journal = {Cancer science},
  year = {2026},
  month = oct,
  doi = {10.1111/cas.70557},
  url = {https://europepmc.org/article/MED/42893963},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - CDK4/6 Inhibitors and Curcumin Synergistically Suppress HER2- Breast Cancer via Lethal ROS and Inhibition of Metastasis.
AU  - Chenyu Wang
AU  - Yiqin Zou
AU  - Chunyu Chang
AU  - Siyue Liu
AU  - Xiankun Ke
AU  - Liang Hu
AU  - Di Wang
AU  - Yukang Lu
AU  - Shiwen Luo
AU  - Sijian Huang
AU  - Yilan Hu
AU  - Wenqi Yu
AU  - Aiping Deng
AU  - Ming Yue
AU  - Jue Jiang
PY  - 2026
DA  - 2026/10/18
JO  - Cancer science
DO  - 10.1111/cas.70557
UR  - https://europepmc.org/article/MED/42893963
AB  - CDK4/6 inhibitors represent a key therapy for HR+/HER2- breast cancer, yet resistance and limited efficacy in triple-negative breast cancer (TNBC) remain significant challenges. Using a self-established drug combination prediction platform, we identified a strong synergy between the CDK4/6 inhibitor palbociclib and the natural compound curcumin across both HR+/HER2- and TNBC models, an effect that was also observed with ribociclib. Mechanistically, the combination led to a collapse of redox homeostasis. Despite upregulating transcriptional antioxidant responses, the treatment downregulated critical ROS-detoxifying enzymes (e.g., GPX4) and depleted glutathione. This imbalance induced lethal oxidative stress, lipid peroxidation, and extensive DNA damage. Furthermore, excessive ROS accumulation contributed to suppression of epithelial-mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N-acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox-based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+/HER2- breast cancer and TNBC.
SN  - 1347-9032
SN  - 1349-7006
ER  -