Abstract
ObjectiveIn this study, the anticancer mechanisms of MT-4 were examined in A2780 and multidrug-resistant NCI-ADR/res human ovarian cancer cell lines.MethodsTo 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.ResultsMT-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.ConclusionThese findings indicate that MT-4 could be a potential lead compound for the treatment of multidrug-resistant ovarian cancer.
Highlights
Ovarian cancer is a major contributor of tumor malignancy in women [1]
We found that p38 Mitogen-activated protein kinases (MAPKs) pathway activation was involved in MT-4-induced apoptosis
Treatment of cells with SB203580 or overexpression of dominant negative (DN)-p38 or wild-type HSP27 reduced PARP cleavage caused by MT-4
Summary
Over 90% of ovarian cancer deaths are caused by drug resistance and tumor metastasis. Drug resistance frequently develops and leads to treatment failure. Drug resistance develops through several mechanisms, including pharmacokinetics, tumor microenvironment, and tumor cell-specific pathways. The most common reason for the development of drug resistance is overexpression of ATP-binding cassette (ABC) transporters such as p-glycoprotein (p-gp). Besides ABC transporters, other mechanisms of resistance include cell cycle alteration, drug detoxification, apoptosis impairment, and oncoprotein deregulation. Heat shock proteins (HSPs) can significantly increase resistance to chemotherapy [3]. It has been shown that HSP27 increases tumor growth, metastasis, and resistance to chemotherapy in numerous types of tumors, including breast, colon, ovarian, and head and neck tumors [3,4,5,6]
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