ABSTRACT
RNAbinding protein Musashi2 (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 nonsmall 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.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Depsipeptides/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Lung Neoplasms/genetics , RNA-Binding Proteins/genetics , Thiazoles/pharmacology , Adult , Aged , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Depsipeptides/chemistry , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Lung Neoplasms/drug therapy , Male , Mice , Middle Aged , Models, Molecular , Molecular Docking Simulation , Protein Conformation , RNA-Binding Proteins/antagonists & inhibitors , RNA-Binding Proteins/chemistry , Thiazoles/chemistry , Up-Regulation/drug effectsABSTRACT
Mangosteen (Garcinia mangostana Linn.) is a well-known tropical tree indigenous to Southeast Asia. Its fruit's pericarp abounds with a class of isoprenylated xanthones which are referred as mangostins. Numerous in vitro and in vivo studies have shown that mangostins and their derivatives possess diverse pharmacological activities, such as antibacterial, antifungal, antimalarial, anticarcinogenic, antiatherogenic activities as well as neuroprotective properties in Alzheimer's disease (AD). This review article provides a comprehensive review of the pharmacological activities of mangostins and their derivatives to reveal their promising utilities in the treatment of certain important diseases, mainly focusing on the discussions of the underlying molecular targets/pathways, modes of action, and relevant structure-activity relationships (SARs). Meanwhile, the pharmacokinetics (PK) profile and recent toxicological studies of mangostins are also described for further druggability exploration in the future.
Subject(s)
Anti-Infective Agents/pharmacology , Antioxidants/pharmacology , Cardiovascular Agents/pharmacology , Garcinia mangostana/chemistry , Plant Extracts/pharmacology , Protective Agents/pharmacology , Xanthones/pharmacology , Animals , Anticarcinogenic Agents/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Fruit/chemistry , Humans , Neuroprotective Agents/pharmacology , PhytotherapyABSTRACT
Cancer chemoprevention is a promising strategy taken to block, reverse, or retard carcinogenesis. α-Mangostin, a natural xanthone isolated from the pericarps of mangosteen, represents one of the most studied chemopreventive agents. This compound has been reported to interfere with all the major stages of carcinogenesis: initiation, promotion, and progression. A number of mechanisms have been proposed for its anticarcinogenic activities. This review summarizes the current knowledge on the mechanisms that contribute to the observed activity of α-mangostin related to (i) modulation of carcinogenic biotransformation and mitigation of oxidative damage, (ii) induction of growth arrest and apoptosis, (iii) suppression of angiogenesis and metastasis, and (iv) combination with clinical chemotherapy drugs enhancing their efficacy and decreasing the toxic side effects. In addition, pharmacokinetic and toxicological studies of α-mangostin have also been highlighted in this review. Despite an overwhelming amount of knowledge in preclinical studies, there was almost no translation of α-mangostin into the clinic. It is hoped that continuous extensive and profound research will lead to the application of α-mangostin from experimental studies to evidence-based, clinically applicable pharmacotherapy.
