Differential dose–response effect of cyclosporine A in regulating apoptosis and autophagy markers in MCF-7 cells

Shoib Siddiqui, Rawad Hodeify, Shimy Mathew, Seba Alsawaf, Anood Alghfeli, Rachel Matar, Maxime Merheb, John Marton, Hussain AbdulKarim Al Zouabi, Dhiviya Prabaa Muthuirulandi Sethuvel, Naveen Kumar Devanga Ragupathi, Cijo George Vazhappilly

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclosporine A (CsA) is an immunosuppressant primarily used at a higher dosage in transplant medicine and autoimmune diseases with a higher success rate. At lower doses, CsA exhibits immunomodulatory properties. CsA has also been reported to inhibit breast cancer cell growth by downregulating the expression of pyruvate kinase. However, differential dose–response effects of CsA in cell growth, colonization, apoptosis, and autophagy remain largely unidentified in breast cancer cells. Herein, we showed the cell growth-inhibiting effects of CsA by preventing cell colonization and enhancing DNA damage and apoptotic index at a relatively lower concentration of 2 µM in MCF-7 breast cancer cells. However, at a higher concentration of 20 µM, CsA leads to differential expression of autophagy-related genes ATG1, ATG8, and ATG9 and apoptosis-associated markers, such as Bcl-2, Bcl-XL, Bad, and Bax, indicating a dose–response effect on differential cell death mechanisms in MCF-7 cells. This was confirmed in the protein–protein interaction network of COX-2 (PTGS2), a prime target of CsA, which had close interactions with Bcl-2, p53, EGFR, and STAT3. Furthermore, we investigated the combined effect of CsA with SHP2/PI3K-AKT inhibitors showing significant MCF-7 cell growth reduction, suggesting its potential to use as an adjuvant during breast cancer therapy.
Original languageEnglish
Pages (from-to)2049-2060
Number of pages12
JournalInflammopharmacology
Volume31
Issue number4
DOIs
Publication statusPublished - 19 May 2023

Keywords

  • Apoptosis
  • Autophagy
  • Breast cancer
  • COX-2
  • Cyclosporine A
  • DNA damage

Fingerprint

Dive into the research topics of 'Differential dose–response effect of cyclosporine A in regulating apoptosis and autophagy markers in MCF-7 cells'. Together they form a unique fingerprint.

Cite this