ex-527 and Breast-Neoplasms

Tumor environmental cytokines, such as IL-6, has a major role in the outcome of radiation and chemotherapy. In this study, we hypothesized that IL-6 mediates its effects via SIRT1 as a protein deacetylase and activator of phosphatidylinositol-3 kinase pathways. In the present study, we evaluated the effects of the novel dual inhibitor of phosphatidylinositol-3 kinase/mammalian target of rapamycin, NVP-BEZ235, and SIRT1 inhibitor and activator plus radiotherapy in breast cancer cells treated with IL-6. Here, IL-6 untreated/pretreated human breast cancer cells were cultured with single or combination of NVP-BEZ235 and/or SIRT1 activator (SRT1720)/inhibitor (EX-527) under radiotherapy condition. After all treatments, the MTT assay and flow cytometry assay were used to explore cell viability and the ability of our treatments in altering cancer stem cells (CSCs) population or cellular death (apoptosis + necrosis) induction. Simultaneous exposure to NVP-BEZ235 and SRT1720 sensitized breast cancer cells to radiotherapy but elevated CSCs. Treatment with IL-6 for 2 weeks significantly decreased CSCs population. Activation of SIRT1 via SRT1720 in combination with NVP-BEZ235 significantly decreased breast cancer cells viability in IL-6 pretreatment cultures. Inhibition of SIRT1 via EX-527 diminished the beneficial effects of IL-6 pretreatment. The combination of NVP-BEZ235 and SRT1720 as a SIRT1 activation could effectively decrease breast cancer cells population and augments the efficacy of radiotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interleukin-6; MCF-7 Cells; Neoplastic Stem Cells; Quinolines; Radiation-Sensitizing Agents; Sirtuin 1

Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC

Topics: Acetamides; Antineoplastic Agents; Breast; Breast Neoplasms; Drug Discovery; Female; Histone Deacetylase Inhibitors; Humans; MCF-7 Cells; Molecular Docking Simulation; Pyrimidines; Sirtuin 2; Structure-Activity Relationship; Tubulin

The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzoquinones; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Dibenzocycloheptenes; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockdown Techniques; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Lactams, Macrocyclic; MCF-7 Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Resorcinols; Sirtuin 1