oxadiazoles and Mesothelioma

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC

Topics: Antineoplastic Agents; Apoptosis; Benzylamines; Caspase 3; Caspase 7; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Forkhead Box Protein O1; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Inhibitory Concentration 50; Mesothelioma; Oxadiazoles; Phosphorylation; Phosphorylcholine; Pleural Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Quinoxalines; Sulfonamides; Thiadiazoles; Thiophenes

Survivin, which is highly expressed and promotes cell survival in diffuse malignant peritoneal mesothelioma (DMPM), exclusively relies on exportin 1 (XPO1/CRM1) to be shuttled into the cytoplasm and perform its anti-apoptotic function. Here, we explored the efficacy of Selective Inhibitors of Nuclear Export (SINE), KPT-251, KPT-276 and the orally available, clinical stage KPT-330 (selinexor), in DMPM preclinical models. Exposure to SINE induced dose-dependent inhibition of cell growth, cell cycle arrest at G1-phase and caspase-dependent apoptosis, which were consequent to a decrease of XPO1/CRM1 protein levels and the concomitant nuclear accumulation of its cargo proteins p53 and CDKN1a. Cell exposure to SINE led to a time-dependent reduction of cytoplasmic survivin levels. In addition, after an initial accumulation, the nuclear protein abundance progressively decreased, as a consequence of an enhanced ubiquitination and proteasome-dependent degradation. SINE and the survivin inhibitor YM155 synergistically cooperated in reducing DMPM cell proliferation. Most importantly, orally administered SINE caused a significant anti-tumor effect in subcutaneous and orthotopic DMPM xenografts without appreciable toxicity. Overall, we have demonstrated a marked efficacy of SINE in DMPM preclinical models that may relay on the interference with survivin intracellular distribution and function. Our study suggests SINE-mediated XPO1/CRM1 inhibition as a novel therapeutic option for DMPM.

Topics: Acrylamides; Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Exportin 1 Protein; G1 Phase Cell Cycle Checkpoints; Humans; Hydrazines; Inhibitor of Apoptosis Proteins; Karyopherins; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, SCID; Neoplasm Proteins; Oxadiazoles; Peritoneal Neoplasms; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; Survivin; Thiazoles; Triazoles; Tumor Suppressor Protein p53

Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum(II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO-211H, MPP89, MM-B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC(50) values in the low micromolar range (IC(50) between 1 and 4 μM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspases; Cell Death; Cell Line, Tumor; Cisplatin; Drug Synergism; Glutathione; Glutathione Disulfide; Glutathione S-Transferase pi; Humans; Inhibitory Concentration 50; MAP Kinase Kinase 4; MCF-7 Cells; Mesothelioma; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Oxadiazoles; p38 Mitogen-Activated Protein Kinases; Pleural Neoplasms