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PLoS One. 2015 Apr 14;10(4):e0123819. doi: 10.1371/journal.pone.0123819. eCollection 2015.

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

Author information

1
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
2
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
3
National Research Institute of Chinese Medicine, Taipei, Taiwan.
4
Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei, Taiwan.

Abstract

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.

PMID:
25874627
PMCID:
PMC4397017
DOI:
10.1371/journal.pone.0123819
[Indexed for MEDLINE]
Free PMC Article

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