Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439

Abstract

Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting effects. We find that not only the PI3Kα- and PI3kβ-isoforms, but also PI3Kδ, are associated with the epithelial-mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate cancer. This suggests that cotargeting PI3Kα/β/δ could preempt the rebound activation of the parallel pathways induced by α- or β-isoform-selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3Kα/β/δ inhibitor, is highly effective in inhibiting null prostate cancer growth and preventing EMT in the mutant metastatic model. The anti-PI3Kδ property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor. .

The APE1 redox inhibitor E3330 reduces collective cell migration of human breast cancer cells and decreases chemoinvasion and colony formation when combined with docetaxel

“…E3330 was the first APE1 redox inhibitor to be identified, [25] and it has been the most widely studied. As described in the literature, at commonly used inhibitory concentrations of the APE1 redox function (e.g., up to 50 μm), [14,17,32,[46][47][48] E3330 did not interfere with APE1 endonuclease activity. [31,32,49] We also performed a fluorescence-based endonuclease activity assay [50] and confirmed that E3330 at 30 μm did not inhibit APE1 DNA repair function (data not shown).…”

“…[6,7] APE1 is usually referred as a dual-function protein because it has also an independent role as a reduction/oxidation signalling protein, modulating the activation of several transcription factors through the reduction of cysteine residues in their DNA-binding domains. Consequently, APE1 regulates the ability of transcription factors, such as nuclear factor-кB (NF-кB), [8] activator protein 1 (AP-1), [9] early growth response protein-1 (Egr-1), [10,11] hypoxia-inducible factor 1α (HIF-1α), [12][13][14] p53, [15,16] signal transducer and activator of transcription 3 (STAT3) [17] among others, to bind to their specific DNA sequence and promote the expression of genes implicated in cancer cell survival, proliferation, migration/invasion, angiogenesis and metastases formation. [6,7] More recently, the redox function of APE1 has been shown to be involved in the regulation of WNT/β-catenin signalling pathway in pancreatic cancer cells.…”

“…(2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4cyclohexadien-1-yl)methylene] undecanoic acid (E3330) ( Figure 1) is a quinone derivative already described as a direct inhibitor of APE1 redox function [7,25] which has been used in different cell-based [14,[26][27][28] and in in vivo [29,30] assays revealing its therapeutic potential. The nature of the E3330-APE1 interaction has been widely studied to unveil the mechanism of the inhibition of APE1's redox activity.…”

“…[28] Moreover, E3330 also impaired the migration and the endothelial cell tube formation of retinal vascular endothelial cells isolated from mice [30] as well as mitigated the progression of choroidal neovascularization in mouse eyes, supporting its role in the inhibition of angiogenesis. [34,35] In addition, E3330 has been shown to decrease the growth [14,17,18,29] and migration of human pancreatic cancer cells in in vitro models. [14] The evaluation of this compound in a pancreatic tumour xenograft model revealed a decrease in tumour growth rate and promising pharmacokinetic and pharmacodynamic properties.…”

“…[34,35] In addition, E3330 has been shown to decrease the growth [14,17,18,29] and migration of human pancreatic cancer cells in in vitro models. [14] The evaluation of this compound in a pancreatic tumour xenograft model revealed a decrease in tumour growth rate and promising pharmacokinetic and pharmacodynamic properties. [29] Overall, these evidences suggest the usefulness of E3330 as a bioactive compound to reduce tumour invasion and metastatic disease in other unexploited cancer models.…”