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Publication Detail

Title: 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.

Authors: Mishra, Rosalin; Yuan, Long; Patel, Hima; Karve, Aniruddha S; Zhu, Haizhou; White, Aaron; Alanazi, Samar; Desai, Pankaj; Merino, Edward J; Garrett, Joan T

Published In Int J Mol Sci, (2021 Feb 19)

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 colony 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 inhibited 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.

PubMed ID: 33669867 Exiting the NIEHS site

MeSH Terms: Animals; Anthracyclines/pharmacology; Anthracyclines/therapeutic use*; Breast Neoplasms/drug therapy*; Breast Neoplasms/pathology*; Cell Line, Tumor; Cell Movement/drug effects; Cell Proliferation/drug effects; Cell Survival/drug effects; Collagen; DNA Damage*; Doxorubicin/pharmacology; Doxorubicin/therapeutic use; Drug Combinations; Female; Fibroblasts/drug effects; Fibroblasts/pathology; Furans/pharmacokinetics; Furans/pharmacology; Furans/therapeutic use; Humans; Laminin; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases/metabolism*; Prodrugs/pharmacology; Prodrugs/therapeutic use*; Proteoglycans; Pyridines/pharmacokinetics; Pyridines/pharmacology; Pyridines/therapeutic use; Pyrimidines/pharmacokinetics; Pyrimidines/pharmacology; Pyrimidines/therapeutic use; Reactive Oxygen Species/metabolism*; Signal Transduction*

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