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2-Methoxyestradiol Induces G2/M Arrest and Apoptosis in Prostate Cancer

https://doi.org/10.1006/bbrc.2001.5320Get rights and content

Abstract

Few therapeutic treatment options are available for patientssuffering from metastatic androgen-independent prostate cancer. We investigated the ability of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferation of a variety of human prostate cancer cell lines in vitro and to inhibit the growth of androgen-independent prostate cancer in a transgenic mouse model in vivo. Our results showed that 2-methoxyestradiol is a powerful growth inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cell flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked accumulation of cells in the G2/M phase of the cell cycle and an increase in the sub-G1 fraction (apoptotic). In addition, staining for annexin V, changes in nuclear morphology, and inhibition of caspase activity support a role for apoptosis. More importantly, we showed that 2-methoxyestradiol inhibits prostate tumor progression in the Gγ/T-15 transgenic mouse model of androgen-independent prostate cancer without toxic side effects. These results in cell culture and an animal model support investigations into the clinical use of 2-methoxyestradiolin patients with androgen-independent prostate cancer.

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      Earlier studies with other microtubule inhibitors have shown that microtubule disruption would lead to cell cycle arrest and ultimately apoptosis (reviewed in Refs. [17]). It is of note that most earlier studies, which were based on flow cytometric analysis of different cell populations, reported that treatment of human cancer cells with 2-methoxyestradiol increases the combined G2/M cell populations [18,19]. However, our earlier study based on morphological analysis revealed that 2-methoxyestradiol induces predominantly mitotic prometaphase arrest in human cancer cells, but not G2 phase arrest [20].

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    1

    The first two authors contributed equally to this work.

    2

    Present address: Kuwait University, Faculty of Medicine, P.O. Box 24923, Safat, Kuwait 13110.

    3

    To whom correspondence may be addressed at VAMC, GRECC (11-GRC), 1201 NW 16 Street, Miami, FL 33125. Fax: (305) 324-3365. E-mail: [email protected].

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