Indomethacin Suppresses Cisplatin-Enriched Stem-Like Breast Cancer Cells
Through Modulating MicroRNAs Expression and Stimulating Antitumor
Immunity
Abstract
Background and Purpose: Cancer resistance to chemotherapy is a clinical
dilemma that eventually leads to increased mortality. It is widely
accepted that cancer stem cells (CSCs) have a pivotal role in the
development of resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs)
have shown a promise to combat CSCs, thus, we addressed for the first
time the effect of indomethacin on cisplatin (CDDP)-resistant murine
breast cancer along with the relevant mechanisms. Experimental Approach:
The murine mammary adenocarcinoma, Ehrlich ascites carcinoma (EAC)
cells, were made resistant by exposure to CDDP and the surviving cells
were then analyzed by flow cytometry for the breast CSCs markers
(CD44+CD24-). CDDP heavily enriched the CSCs population which was
subsequently injected into mice. After induction of tumors, mice were
treated with CDDP, or indomethacin, or co-treatment with both drugs, or
left untreated. Upon termination of the treatment period, blood samples
were collected to measure the percentage of CSCs markers (CD44, CD24,
SCa-1) and the immune cells (CD4+, CD62L+, and CD117+). The tumors were
excised and analyzed for the relative expression of drug
resistance-mediating miRNAs (miR-7, miR-21, miR-22, and miR-145) in
addition to histopathological examination. Key Results: Indomethacin
drastically diminished the tumorigenicity of CDDP-resistant cells along
with enhancing its sensitivity to CDDP which were correlated with its
suppressing ability of CD44+CD24- cells and manipulating effect on
miRNAs expression. Besides, indomethacin expanded the pool of immune
cells that impart antitumor response. Conclusion and Implications:
Indomethacin through targeting CSCs may confer better outcome than
conventional chemotherapeutics in the treatment of resistant breast
cancer.