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 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.

RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells

“…In breast cancer cells RIDR-PI-103 in combination with doxorubicin inhibited cell proliferation, impaired PI3K signaling, and activated DNA damage [30]. Use of RIDR-PI-103 in cord blood cells and fibroblasts did not demonstrate toxicity [29,30]. Similarly in our study, we observed that RIDR-PI-103 had increased specificity in TDR cells over melanocytes at 5 µM (Figs.…”

“…A boron-containing bioisostere of PI-103 offered improved bioavailability [28]. ROS-induced drug release (RIDR)-PI-103 is a prodrug of PI-103, which in presence of high ROS releases the biologically active component, PI-103 [29,30].…”

Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway

“…According to this theory, the high ROS production in cancer cells causes malfunction of the mitochondrial membrane, inhibits the PI3K/Akt protein kinase, and leads to the Raf-1/ERK1/2 signaling pathway inhibition. Finally, apoptosis is induced, and cell survival, proliferation, and metastasis are arrested. ,− …”

Smart Nanoparticles for Breast Cancer Treatment Based on the Tumor Microenvironment

“…Recently, great progress has been made in the understanding of ROS biology, and there is increasing evidence that the effects of ROS are gradient-dependent, with a threshold of habituation, which affects their signal transduction and toxicity induction function, thus resulting in either "good" or "bad" ROS (33). For example, ROS play a key role in the activation of tumor-promoting signaling pathways (64,66,67). Moreover, abnormal production of ROS and ineffective neutralization of excessive ROS levels can lead to tumor growth and progression through different signaling pathways, including phosphatidylinositol 3kinase/protein kinase inhibitor/mammalian target of rapamycin (PI3/Akt/mTOR), vascular endothelial growth factor (VEGF)/ VEGF receptor, phosphatase and tensin congeners (PTEN), and matrix metalloproteinase (MMP) pathways (68).…”