largazole and Lung-Neoplasms

RNA‑binding protein Musashi‑2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non‑small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients. Molecular docking analysis demonstrated that the small compound largazole binds to and may be a potential inhibitor of MSI2. Largazole markedly decreased the protein and mRNA levels of MSI2 and suppressed its downstream mammalian target of rapamycin signaling pathway. Largazole also inhibited the proliferation and induced apoptosis of NSCLC and chronic myeloid leukemia (CML) cells (including bone marrow mononuclear cells harvested from CML patients). These results indicate that MSI2 is an emerging therapeutic target for NSCLC and CML, and the MSI2 inhibitor largazole may hold promise as a treatment for these malignancies.

Topics: Adult; Aged; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Depsipeptides; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lung Neoplasms; Male; Mice; Middle Aged; Models, Molecular; Molecular Docking Simulation; Protein Conformation; RNA-Binding Proteins; Thiazoles; Up-Regulation

Largazole is a potent class I-selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product.. The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model was investigated.. In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl-substituted Largazole analogs had low-nanomolar/high-picomolar antiproliferative activity, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5 mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetic parameters. In an A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI%) of 32, 44, and 66%, respectively. Largazole peptide isostere treatment was statistically superior to control (p = 0.002) and to Largazole (p = 0.006). Surprisingly, tumor growth inhibition was not observed with the potent pyridyl-based analogs.. These results establish that replacing the depsipeptide linkage in Largazole with an amide may impart pharmacokinetic and therapeutic advantage and that alternative prodrug forms of Largazole are feasible.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Depsipeptides; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Mice; Mice, Nude; Models, Biological; Molecular Structure; Pyridines; Structure-Activity Relationship; Thiazoles; Xenograft Model Antitumor Assays