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Research Articles: Therapeutics

Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice

¹ Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia; ² Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China; and ³ BR Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India

Requests for reprints: Ritu Aneja or Harish C. Joshi, Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. Phone: 404-727-0445; Fax: 404-727-6256. E-mail: raneja{at}emory.edu or joshi{at}cellbio.emory.edu.

Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 µmol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G₂-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer. [Mol Cancer Ther 2006;5(9):2366–77]

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Received 4/13/06; revised 6/26/06; accepted 7/12/06.

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