Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice
Open Access
- 1 September 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 5 (9), 2366-2377
- https://doi.org/10.1158/1535-7163.mct-06-0205
Abstract
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]Keywords
This publication has 59 references indexed in Scilit:
- Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast CancerThe Oncologist, 2005
- P21WAF1/CIP1 is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cellsOncogene, 2004
- Paclitaxel-resistant Human Ovarian Cancer Cells Undergo c-Jun NH2-terminal Kinase-mediated Apoptosis in Response to NoscapineJournal of Biological Chemistry, 2002
- Minor Alteration of Microtubule Dynamics Causes Loss of Tension across Kinetochore Pairs and Activates the Spindle CheckpointJournal of Biological Chemistry, 2002
- Multidrug resistance in cancer: role of ATP–dependent transportersNature Reviews Cancer, 2002
- Differential Assembly Kinetics of α-Tubulin Isoforms in the Presence of PaclitaxelBiochemical and Biophysical Research Communications, 1998
- Feedback control of mitosis in budding yeastCell, 1991
- S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule functionCell, 1991
- New Colorimetric Cytotoxicity Assay for Anticancer-Drug ScreeningJNCI Journal of the National Cancer Institute, 1990
- MitosisScience, 1989