15α-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

Abstract

Studies with 15α-methoxypuupehenol (15α-MP), obtained from the extracts of Hyrtios sp., identified putative targets that are associated with its antitumor effects against human glioblastoma (GBM) and breast cancer. In the human GBM (U251MG) or breast cancer (MDA-MB-231) cells, treatment with 15α-MP repressed pY705Stat3 (Signal Transducer and Activator of Transcription 3), pErk1/2 (extracellular signal-regulated kinase), pS147CyclinB1, pY507Alk (Anaplastic lymphoma kinase), and pY478ezrin levels, and induced pS10merlin, without inhibiting pJAK2 (Janus kinase) or pAkt induction. 15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and GBM (U251MG) lines and GBM patient-derived xenograft cells (G22) that harbor aberrantly-active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3fl/fl) lines that do not harbor constitutively-active Stat3, or the Stat3 null (Stat3−/−) mouse astrocytes. 15α-MP-treated U251MG cells have severely impaired F-actin organization and altered morphology, including the cells rounding up, and undergo apoptosis, compared to a moderate, reversible morphology change observed for similarly-treated mouse astrocytes. Treatment further inhibited U251MG or MDA-MB-231 cell proliferation, anchorage-independent growth, colony formation, and migration in vitro, while only moderately or weakly affecting MCF7 cells or normal mouse astrocytes. Oral gavage delivery of 15α-MP inhibited the growth of U251MG subcutaneous tumor xenografts in mice, associated with apoptosis in the treated tumor tissues. Results together suggest the modulation of Stat3, CyclinB1, Alk, ezrin, merlin, and Erk1/2 functions contributes to the antitumor effects of 15α-MP against GBM and breast cancer progression.

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

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Pharmacologic Inhibition of Ezrin-Radixin-Moesin Phosphorylation is a Novel Therapeutic Strategy in Rhabdomyosarcoma

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