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.

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

doi:10.3390/ijms22042088

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.

Highlights

The phosphatidylinositol-3 kinase (PI3K) is a family of lipid kinases
We utilized MDA-MB-231 cells as these triple negative breast cancer (TNBC) cells have increased reactive oxygen species (ROS) compared to other breast cancer cells [26] and could have more activation of the ROS-activated scaffold drug
We found variable sensitivity of cells to ROS-induced drug release (RIDR)-PI-103 (Figure 1)

Summary

Introduction

The phosphatidylinositol-3 kinase (PI3K) is a family of lipid kinases. Class IA PI3Ks are heterodimeric proteins with a p110 catalytic subunit and a p85 regulatory subunit and are involved in carcinogenesis. Within class IA, the genes PIK3CA, PIK3CB, and PI3KCD encode the homologous p110α, p110β, and p110δ isozymes respectively. PI3K is activated upstream by the binding of a ligand to its cognate receptor tyrosine kinase (RTK), which include members of the human epidermal growth factor receptor (HER) family, and insulinlike growth factor 1 (IGF-1) receptor, among others [1,2]. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), which in turn leads to phosphorylation of Protein kinase B, (AKT), a serine/threonine kinase [3]. The PI3K pathway is hyper-activated in >60% of clinical breast cancers due to aberrations in genes encoding HER2, PTEN, PIK3CA, or AKT1-3 [4,5,6]

Methods

Results

Conclusion