MT-4 suppresses resistant ovarian cancer growth through targeting tubulin and HSP27

Autor: Che-Ming Teng, Sunil Kumar, Hui Chen Pai, Shiow Lin Pan, Jing Ping Liou, Chien Chang Shen
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Pyridines
HSP27 Heat-Shock Proteins
lcsh:Medicine
Cell Cycle Proteins
p38 Mitogen-Activated Protein Kinases
Histones
Mice
Tubulin
Aurora Kinase B
lcsh:Science
Heat-Shock Proteins
Ovarian Neoplasms
Multidisciplinary
biology
Caspase 3
Imidazoles
Cell cycle
Cyclin-Dependent Kinases
Tubulin Modulators
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation
Neoplastic
Female
Research Article
Signal Transduction
Antineoplastic Agents
Cyclin B
Protein Serine-Threonine Kinases
Tubulin binding
Cyclin-dependent kinase
Cell Line
Tumor
Proto-Oncogene Proteins
Benzyl Compounds
CDC2 Protein Kinase
Animals
Humans
Viability assay
Cell Proliferation
Cyclin-dependent kinase 1
Cell growth
Carcinoma
lcsh:R
Molecular biology
Xenograft Model Antitumor Assays
Drug Resistance
Neoplasm
Cancer cell
Cancer research
biology.protein
lcsh:Q
Molecular Chaperones
Zdroj: PLoS ONE, Vol 10, Iss 4, p e0123819 (2015)
PLoS ONE
ISSN: 1932-6203
Popis: Objective In this study, the anticancer mechanisms of MT-4 were examined in A2780 and multidrug-resistant NCI-ADR/res human ovarian cancer cell lines. Methods To evaluate the activity of MT-4, we performed in vitro cell viability and cell cycle assays and in vivo xenograft assays. Immunoblotting analysis was carried out to evaluate the effect of MT-4 on ovarian cancer. Tubulin polymerization was determined using a tubulin binding assay. Results MT-4 (2-Methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-ethyl]-phenol), a derivative of moscatilin, can inhibit both sensitive A2780 and multidrug-resistant NCI-ADR/res cell growth and viability. MT-4 inhibited tubulin polymerization to induce G2/M arrest followed by caspase-mediated apoptosis. Further studies indicated that MT-4 is not a substrate of P-glycoprotein (p-gp). MT-4 also caused G2/M cell cycle arrest, accompanied by the upregulation of cyclin B, p-Thr161 Cdc2/p34, polo-like kinase 1 (PLK1), Aurora kinase B, and phospho-Ser10-histone H3 protein levels. In addition, we found that p38 MAPK pathway activation was involved in MT-4-induced apoptosis. Most importantly, MT-4 also decreased heat shock protein 27 expression and reduced its interaction with caspase-3, which inured cancer cells to chemotherapy resistance. Treatment of cells with SB203580 or overexpression of dominant negative (DN)-p38 or wild-type HSP27 reduced PARP cleavage caused by MT-4. MT-4 induced apoptosis through regulation of p38 and HSP27. Our xenograft models also show the in vivo efficacy of MT-4. MT-4 inhibited both A2780 and NCI-ADR/res cell growth in vitro and in vivo. Conclusion These findings indicate that MT-4 could be a potential lead compound for the treatment of multidrug-resistant ovarian cancer.
Databáze: OpenAIRE
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