Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80 mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, 1H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.

• Authors: Pranesh Kumar, Aakriti Agarwal, Ashok K Singh, Anurag Kumar Gautam, Sreemoyee Chakraborti, Umesh Kumar, Dinesh Kumar, Bolay Bhattacharya, Parthasarathi Panda, Biswajit Saha, Tabish Qidwai, Biswanath Maity, Sudipta Saha
• Journal: Regulatory toxicology and pharmacology : RTP (Regul Toxicol Pharmacol) Vol. 109 Pg. 104489 (Dec 2019) ISSN: 1096-0295 [Electronic] Netherlands
• PMID: 31605713 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Indoles
• Phenylcarbamates
• Sulfonamides
• Tosyl Compounds
• Diethylnitrosamine
• Fluorouracil
• zafirlukast

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (blood, metabolism)
• Carcinoma, Hepatocellular (blood, chemically induced, drug therapy, metabolism)
• Cell Survival (drug effects)
• Diethylnitrosamine (toxicity)
• Drug Screening Assays, Antitumor
• Fluorouracil (pharmacology, therapeutic use)
• Humans
• Indoles
• Liver (drug effects, metabolism, pathology)
• Liver Neoplasms, Experimental (blood, chemically induced, drug therapy, metabolism)
• Male
• Metabolomics
• Mitochondria (drug effects, metabolism)
• Phenylcarbamates
• Proton Magnetic Resonance Spectroscopy
• Rats
• Sulfonamides
• Tosyl Compounds (pharmacology, therapeutic use)