Atorvastatin Improves Cisplatin Sensitivity in Breast Cancer Cells

Abdullah Hashmi, MD

September 01, 2022

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed. It found that atorvastatin increases the sensitivity of cisplatin-resistant breast cancer cells by modifying cholesteryl ester homeostasis. The findings suggest cholesterol homeostasis is upregulated as an adaptive response by breast cancer cells and contributes to cancer aggressiveness and chemotherapy resistance.

Key Takeaways

  • The coadministration of cisplatin and atorvastatin reduced breast cancer cell proliferation and viability more than cisplatin alone, especially in triple-negative breast cancer cells.

  • The findings suggest the upregulation of cholesterol homeostasis acts as an adaptive response by breast cancer cells that contributes to aggressiveness and chemotherapy resistance. 

Why This Matters

  • Multiple mechanisms have been associated with the acquisition of a chemo-resistant phenotype by cancer cells, including drug inactivation, drug efflux, apoptosis suppression, and increased DNA repair. However, the role of cholesteryl ester metabolism in cisplatin resistance in breast cancer cells has remained unclear.

  • The results of this study emphasize the important role that cholesterol metabolism plays in breast cancer progression as an adaptive mechanism in response to cisplatin treatment. 

Study Design

  • The study exposed luminal A, triple-negative, and cisplatin-resistant triple-negative cell lines to cisplatin in combination with atorvastatin. 

  • Lipid depletion and low-density lipoprotein (LDL) loading were analyzed using a variety of biochemical and radiometric techniques.

Key Results

  • The study established that cisplatin sensitivity is associated with changes in expression patterns of key players in cholesterol homeostasis. There is a reliance on cholesteryl ester availability by breast cancer cells to resist cisplatin-associated cell death. The upregulation of cholesterol homeostasis is an adaptive response that contributes to aggressiveness and chemotherapy resistance. 

  • Atorvastatin enhanced the cytoxic effect of cisplatin. Atorvastatin impacts cisplatin sensitivity in breast cancer cells by regulating key enzymes involved in cholesteryl-ester metabolism including acetyl-CoA acetyltransferase 1 (ACAT-1). 

  • Cisplatin and atorvastatin reduced breast cancer cell proliferation and viability more than cisplatin alone, especially in triple-negative breast cancer cells. There was reduced synthesis and storage of cholesteryl ester in triple-negative breast cancer cells.

  • In cisplatin-resistant cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared with luminal A and non­­–cisplatin-resistant triple-negative cells. Aberrant ACAT-1 expression may therefore contribute to cisplatin resistance in triple-negative breast cancer cells. 

Limitations

  • Limitations to the study were not discussed by authors.

Disclosures

  • The study received no commercial funding.

  • None of the authors disclosed relevant financial relationships.

This is a summary of a preprint research study, “ Atorvastatin Improves Cisplatin Sensitivity Through Modulation of Cholesteryl Ester Homeostasis in Breast Cancer Cells ,” published Aug. 11 on ResearchSquare.com and led by Andrew Hoy of the University of Sydney, Sydney, Australia. This study has not yet been peer reviewed. 

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