Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

Chen Sun; Pan Liu; Lijian Pei; Mengyun Zhao; Yuguang Huang

doi:10.3389/fonc.2022.837974

Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

Front Oncol. 2022 Mar 28:12:837974. doi: 10.3389/fonc.2022.837974. eCollection 2022.

Authors

Chen Sun^{1

2}, Pan Liu^{2

3

4}, Lijian Pei^{1

2

5}, Mengyun Zhao^{1

2}, Yuguang Huang^{1

2}

Affiliations

¹ Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
² Joint Laboratory of Anesthesia and Pain, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
³ Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
⁴ Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁵ Outcomes Research Consortium, Cleveland, OH, United States.

Abstract

Background: Triple-negative breast cancer (TNBC) is relatively common in women and is associated with a poor prognosis after surgery and adjuvant chemotherapy. Currently, the mechanism underlying the relationship between propofol and breast cancer is controversial and limited to cell apoptosis. Moreover, there are only a few studies on the effect of propofol on the chemotherapeutic sensitivity of TNBC cells. Therefore, this study explored whether propofol and its commonly used clinical formulations affect the proliferation and chemotherapeutic effects on TNBC cells by regulating cell ferroptosis.

Methods: We selected MDA-MB-231 cells, and the effects of propofol, propofol injectable emulsion (PIE), or fospropofol disodium, alone or combined with doxorubicin or paclitaxel on cell viability, apoptosis, intracellular reactive oxygen species (ROS) accumulation, ferroptosis-related morphological changes, intracellular Fe²⁺ levels, and the expression and localization of ferroptosis-related proteins were investigated.

Results: We found that propofol significantly inhibited MDA-MB-231 cell proliferation, and all three propofol formulations augmented the anti-tumor effects of doxorubicin and paclitaxel. The results from the ROS assay, transmission electron microscopy, intracellular Fe²⁺ assay, western blotting, and multiplex immunohistochemistry revealed that propofol not only induced apoptosis but also triggered ferroptosis-related changes, including morphological changes of mitochondria, increased intracellular ROS levels, and intracellular iron accumulation in MDA-MB-231 cells. The ferroptosis-related p53-SLC7A11-GPX4 pathway was also altered under different treatment propofol, doxorubicin, or paclitaxel regimens.

Conclusion: Propofol showed anti-proliferation effects on TNBC cells and could be a potential adjuvant to enhance the chemotherapeutic sensitivity of TNBC cells partly by promoting cell ferroptosis.

Keywords: ferroptosis; fospropofol disodium; propofol; propofol injectable emulsion; triple-negative breast cancer.