Cucurbitacin B potently suppresses non-small-cell lung cancer growth: identification of intracellular thiols as critical targets.

Abstract

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB's cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB's cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.

• Authors: Hina Kausar, Radha Munagala, Shyam S Bansal, Farrukh Aqil, Manicka V Vadhanam, Ramesh C Gupta
• Journal: Cancer letters (Cancer Lett) Vol. 332 Issue 1 Pg. 35-45 (May 10 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23340170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Antioxidants
• HSP27 Heat-Shock Proteins
• HSPB1 protein, human
• Heat-Shock Proteins
• Molecular Chaperones
• Sulfhydryl Compounds
• Triterpenes
• cucurbitacin B
• p38 Mitogen-Activated Protein Kinases
• Glutathione
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Actin Cytoskeleton (drug effects, metabolism)
• Animals
• Antineoplastic Agents, Phytogenic (metabolism, pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Glutathione (metabolism)
• HSP27 Heat-Shock Proteins (metabolism)
• Heat-Shock Proteins
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mass Spectrometry
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism, pathology)
• Molecular Chaperones
• Oxidation-Reduction
• Signal Transduction (drug effects)
• Spectrophotometry, Ultraviolet
• Spectroscopy, Fourier Transform Infrared
• Sulfhydryl Compounds (metabolism)
• Time Factors
• Triterpenes (metabolism, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism)