Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice.
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 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 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.
Aneja
Ritu
R
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. raneja@emory.edu
Zhou
Jun
J
Zhou
Binfei
B
Chandra
Ramesh
R
Joshi
Harish C
HC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D024161:Collagen Type XI / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007546:Isoquinolines / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D009665:Noscapine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C499319:COL11A2 protein, human; D024161:Collagen Type XI; D004149:Dioxoles; C510553:EM011 compound; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D009665:Noscapine; D045304:Cytochromes c; D053148:Caspase 3