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J Ethnopharmacol. 2011 Oct 11;137(3):1283-90. doi: 10.1016/j.jep.2011.07.056. Epub 2011 Aug 4.

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

Author information

1
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Tamoxifen 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 METHODS:

Cell growth and ERα-related pathways were studied. The effects of annonacin were tested in MCF-7 xenografts in nude mice.

RESULTS:

In ERα-positive MCF-7 cells, annonacin (half-effective dose ED(50) = 0.31 μM) and 4-hydroxytamoxifen (ED(50) = 1.13 μM) decreased cell survival whereas annonacin (0.5-1 μM) increased cell death at 48 h. Annonacin and 4-hydroxytamoxifen were additive in inhibiting cell survival. Annonacin (0.1 μM) induced G(0)/G(1) growth arrest while increasing p21(WAF1) and p27(kip1) and decreasing cyclin D1 protein expression. Annonacin (0.1μM) decreased cyclin D1 protein expression more than 4-hydroxytamoxifen (1 μM). Annonacin (0.1 μM) increased apoptosis while decreasing Bcl-2 protein expression. The combination of annonacin (0.1 μM) and 4-hydroxytamoxifen (1 μM) decreased Bcl-2 protein expression and ERα transcriptional activity more than annonacin (0.1 μM) 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.

CONCLUSIONS:

Annonacin 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.

PMID:
21840388
DOI:
10.1016/j.jep.2011.07.056
[Indexed for MEDLINE]

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