Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells

Abstract

Ethnopharmacological relevanceTamoxifen resistance is common in estrogen receptor-α (ERα)-positive breast cancers. Pawpaw and soursop are anticancer annonaceous plants in complementary medicine. Thus, we studied the effects of annonacin, an annonaceous acetogenin, in breast cancer cells. Materials and MethodsCell growth and ERα-related pathways were studied. The effects of annonacin were tested in MCF-7 xenografts in nude mice. ResultsIn ERα-positive MCF-7 cells, annonacin (half-effective dose ED50=0.31μM) and 4-hydroxytamoxifen (ED50=1.13μM) decreased cell survival whereas annonacin (0.5-1μM) increased cell death at 48h. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival. Annonacin (0.1μM) induced G0/G1 growth arrest while increasing p21WAF1 and p27kip1 and decreasing cyclin D1 protein expression. Annonacin (0.1μM) decreased cyclin D1 protein expression more than 4-hydroxytamoxifen (1μM). Annonacin (0.1μM) increased apoptosis while decreasing Bcl-2 protein expression. The combination of annonacin (0.1μM) and 4-hydroxytamoxifen (1μM) decreased Bcl-2 protein expression and ERα transcriptional activity more than annonacin (0.1μM) did alone. Annonacin, but not 4-hydroxytamoxifen, decreased ERα protein expression. Moreover, annonacin decreased phosphorylation of ERK1/2, JNK and STAT3. In nude mice, annonacin decreased MCF-7 xenograft tumor size at 7–22 days. Moreover, annonacin decreased ERα, cyclin D1 and Bcl-2 protein expression in the xenograft at 22 days. ConclusionsAnnonacin induced growth arrest and apoptosis in ERα-related pathways in MCF-7 cells. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival and ERα transcriptional activity. Moreover, annonacin attenuated MCF-7 xenograft tumor growth while inhibiting ERα, cyclin D1 and Bcl-2 protein expressions in nude mice.