rg7388 and Breast-Neoplasms

Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately, histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA, or vorinostat, MK0683) have been emerging as a new class of drugs with promising therapeutic benefits in controlling cancer growth and metastasis. The small molecule RG7388 (idasanutlin, R05503781) is a newly developed inhibitor that is specific for an oncogene-derived protein called MDM2, which is also in clinical trials for the treatment of various types of cancers. These two drugs have shown the ability to induce p21 expression through distinct mechanisms in MCF-7 and LNCaP cells, which are reported to have wild-type TP53. Our understanding of the molecular mechanism whereby SAHA and RG7388 can induce cell cycle arrest and trigger cell death is still evolving. In this study, we performed experiments to measure the cell cycle arrest effects of SAHA and RG7388 using MCF-7 and LNCaP cells.. The cytotoxicity, cell cycle arrest, and apoptosis/necroptosis effects of the SAHA and RG7388 treatments were assessed using the Trypan Blue dye exclusion (TBDE) method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence assay with DEVD-amc substrate, and immunoblotting methods.. The RG7388 treatment was able to induce cell death by elevating p21. Our results from MCF-7 and LNCaP cells confirmed that SAHA and RG7388 treatments were able to induce cell death via a combination of cell cycle arrest and cytotoxic mechanisms. We speculate that our findings could lead to the development of newer treatments for breast and prostate cancers with drug combinations including HDACi.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Drug Discovery; Female; Histone Deacetylase Inhibitors; Humans; Male; MCF-7 Cells; para-Aminobenzoates; Prostatic Neoplasms; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Tumor Suppressor Protein p53; Vorinostat

Venetoclax (ABT-199) and idasanutlin (RG7388) are efficient anticancer drugs targeting two essential apoptosis markers, Bcl-2 and MDM2, respectively. Recent studies have shown that the combination of these two drugs leads to remarkable enhancement of anticancer efficacy, both in vitro and in vivo. In an attempt to disclose the relationships of their protein targets, competitive affinity-based proteome profiling coupled with bioimaging was employed to characterize their protein targets in the same cancer cell line and tumor tissue. A series of protein hits, including ITPR1, GSR, RER1, PDIA3, Apoa1, and Tnfrsf17 were simultaneously identified by pull-down/LC-MS/MS with the two sets of affinity-based probes. Dual imaging was successfully carried out, with the simultaneous detection of Bcl-2 and MDM2 expression in various cancer cells. This could facilitate the novel diagnostic and therapeutic strategies of dual targeting of Bcl-2/MDM2.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorescent Dyes; Humans; MCF-7 Cells; Models, Molecular; Molecular Structure; Optical Imaging; para-Aminobenzoates; Proteome; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Structure-Activity Relationship; Sulfonamides