Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline...

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Reactive oxygen species (ROS)-induced drug release offers targeted cancer therapy.
• Pan-PI3K inhibitor (PI-103) is a potential anti-cancer agent, but its efficacy requires targeted delivery.
• RIDR-PI-103 is a novel prodrug designed for ROS-triggered release of PI-103.

Purpose of the Study:

• To evaluate the efficacy and bioavailability of RIDR-PI-103 in breast cancer models.
• To assess the in vitro cytotoxicity and anti-migratory effects of RIDR-PI-103.
• To investigate the molecular mechanisms of RIDR-PI-103 in combination with doxorubicin.

Main Methods:

• In vitro cell viability assays on breast cancer and normal cells.
• Colony formation, proliferation, and migration assays.
• Western blot analysis for AKT activation and DNA damage markers.
• Pharmacokinetic studies in C57BL/6J mice.

Main Results:

• RIDR-PI-103 demonstrated selective toxicity towards breast cancer cell lines (MDA-MB-453, MDA-MB-231, MDA-MB-361) compared to normal cells.
• Combination treatment with doxorubicin significantly suppressed cancer cell growth and proliferation.
• RIDR-PI-103 modulated AKT signaling and DNA damage response pathways (inhibited p-AktS473, upregulated p-CHK1/2 and p-P53).
• Pharmacokinetic studies in mice achieved therapeutic concentrations (~200 ng/mL) with a 10-hour half-life.

Conclusions:

• RIDR-PI-103 exhibits promising anti-cancer activity against breast cancer cells.
• The prodrug demonstrates potential for targeted drug delivery and combination therapy.
• RIDR-PI-103 warrants further investigation as a therapeutic agent for breast cancer treatment.