Phosphoinositide 3‐kinase (Pi3k) reactive oxygen species (ros)‐activated prodrug in combination with anthracycline impairs pi3k signaling, increases dna damage response and reduces breast cancer cell growth

Abstract

RIDR‐PI‐103 is a novel reactive oxygen species (ROS)‐induced drug release prodrug with a self‐cyclizing moiety linked to a pan‐PI3K inhibitor (PI‐103). Under high ROS, PI‐103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR‐PI‐103 in breast cancer remains unexplored. Cell viability of RIDR‐PI‐103 was assessed on breast cancer cells (MDA‐ MB‐231, MDA‐MB‐361 and MDA‐MB‐453), non‐tumorigenic MCF10A and fibroblasts. Matrigel col-ony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR‐PI‐103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR‐PI‐103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T1/2 of RIDR‐PI‐103. MDA‐MB‐453, MDA‐MB‐231 and MDA‐MB‐361 cells were sensitive to RIDR‐PI‐103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR‐PI‐103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR‐PI‐103 inhib-ited p‐AktS473, upregulated p‐CHK1/2 and p‐P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR‐PI‐103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T1/2. (4) The prodrug RIDR‐PI‐103 could be a potential therapeutic for treatment of breast cancer patients.