title: Cucurbitacin B Alters the Expression of Tumor-Related Genes by Epigenetic Modifications in NSCLC and Inhibits NNK-Induced Lung Tumorigenesis.
abstract: Non-small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors is effective against various cancers, including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Furthermore, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer.
authors: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Samriddhi
authors: S
authors: Shukla
authors: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Sajid
authors: S
authors: Khan
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Sudhir
authors: S
authors: Kumar
authors: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Sonam
authors: S
authors: Sinha
authors: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Mohd
authors: M
authors: Farhan
authors: Division of Laboratory Animals, CSIR-Central Drug Research Institute, Lucknow, India.
authors: Himangsu K
authors: HK
authors: Bora
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors: Rakesh
authors: R
authors: Maurya
authors: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. s.musthapa@cdri.res.in.
authors: Syed Musthapa
authors: SM
authors: Meeran
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D026501:Blotting, Southwestern; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052138:Genes, Neoplasm; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D012333:RNA, Messenger; D014315:Triterpenes; C041246:cucurbitacin B; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006655:Histone Deacetylases