In Vitro Investigation of Therapy-Induced Senescence and Senescence Escape in Breast Cancer Cells Using Novel Flow...

Area of Science:

• Oncology
• Cell Biology
• Cancer Therapy

Background:

• Cellular senescence, initially defined as irreversible cell cycle arrest, is challenged by the emergence of proliferative senescence-escaped cancer cells.
• Senescence escape can contribute to resistance against cancer treatments, necessitating further investigation into its mechanisms.

Purpose of the Study:

• To develop novel methods for studying senescence escape and isolating senescence-escaped cells.
• To investigate the role of dipeptidyl peptidase 4 (DPP4/CD26) as a senescence marker and its influence on senescence escape.
• To evaluate the senolytic drug azithromycin and its combination with a DPP4 inhibitor (sitagliptin) in senescent breast cancer cells.

Main Methods:

• Development of flow cytometry-based methods utilizing Ki-67 and CellTrace CFSE for senescence escape studies.
• Investigation of DPP4/CD26 expression in senescent MCF-7 and MDA-MB-231 breast cancer cells.
• Assessment of azithromycin's senolytic effect and its combination with sitagliptin on senescence escape.

Main Results:

• DPP4/CD26 expression was significantly increased in senescent MCF-7 and MDA-MB-231 cells.
• DPP4/CD26 promoted senescence escape in MCF-7 cells but not MDA-MB-231 cells.
• Azithromycin demonstrated a senolytic effect, and its combination with sitagliptin synergistically reduced senescent MCF-7 cells and senescence escape.

Conclusions:

• Novel flow cytometry methods aid in studying senescence escape and identifying potential therapeutic targets.
• DPP4/CD26 is a promising marker and potential therapeutic target to reduce senescence escape in cancer.
• Targeting DPP4/CD26 in combination with senolytic agents like azithromycin may offer a strategy to overcome treatment resistance.