Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness

Ping Huang; Huachao Li; Liping Ren; Haimei Xie; Liushan Chen; Yuqi Liang; Yuyu Hu; Heloisa Sobreiro Selistre-de-Araujo; Stergios Boussios; Sachin R Jhawar; Rutao Cui; Qian Zuo; Qianjun Chen

doi:10.21037/tcr-23-1885

Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness

Transl Cancer Res. 2023 Dec 31;12(12):3703-3717. doi: 10.21037/tcr-23-1885. Epub 2023 Dec 21.

Authors

Ping Huang^#^{1

2}, Huachao Li^#², Liping Ren^#², Haimei Xie², Liushan Chen^{2

3}, Yuqi Liang², Yuyu Hu^{2

3}, Heloisa Sobreiro Selistre-de-Araujo⁴, Stergios Boussios^{5

6

7

8}, Sachin R Jhawar⁹, Rutao Cui¹⁰, Qian Zuo², Qianjun Chen^{1

2

3}

Affiliations

¹ State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
² Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
³ Guangdong Academy of Chinese Medicine, Guangzhou, China.
⁴ Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Universidade Federal de São Carlos (UFSCar), São Carlos, Brazil.
⁵ Department of Medical Oncology, Medway NHS Foundation Trust, Kent, UK.
⁶ Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK.
⁷ Kent Medway Medical School, University of Kent, Kent, UK.
⁸ AELIA Organization, Thessaloniki, Greece.
⁹ Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹⁰ Zhejiang University School of Medicine, Hangzhou, China.

^# Contributed equally.

Abstract

Background: Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) Astragalus membranaceus, which can improve the sensitivity of various tumors to chemotherapy drugs. Here, we explored the sensitization effect of ASIV to chemotherapy drug paclitaxel (PTX) in breast cancer from the perspective of CSCs.

Methods: The study included both in vitro and in vivo experiments. CSCs from the breast cancer cell line MCF7 with stem cell characteristics were successfully induced in vitro. Cell viability and proliferation were detected using the Cell Counting Kit-8 (CCK-8) and colony formation assays, and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) methods were performed to detect cell apoptosis. Stemness-related protein expression was determined by western blotting (WB) and immunohistochemistry (IHC). Body weight, histopathology, and visceral organ damage of mice were used to monitor drug toxicity.

Results: The expression of stemness markers including Sox2, Nanog, and ALDHA1 was stronger in MCF7-CSCs than in MCF7. PTX treatment inhibited the proliferation of tumor cells by promoting cell apoptosis, whereas the stemness of breast cancer stem cells (BCSCs) resisted the effects of PTX. ASIV decreased the stemness of BCSCs, increased the sensitivity of BCSCs to PTX, and synergistically promoted PTX-induced apoptosis of breast cancer cells. Our results showed that the total cell apoptosis rate increased by about 25% after adding ASIV compared with BCSCs treated with PTX alone. The in vivo experiments demonstrated that ASIV enhanced the ability of PTX to inhibit the growth of breast cancer. WB and IHC showed that ASIV reduced the stemness of CSCs.

Conclusions: In this study, the resistance of breast cancer to PTX was attributed to the existence of CSCs; ASIV weakened the resistance of MCF7-CSCs to PTX by significantly attenuating the hallmarks of breast cancer stemness and improved the efficacy of PTX.

Keywords: Breast cancer; astragaloside IV (ASIV); cancer stem cells (CSCs); chemotherapy; paclitaxel (PTX).