Antitumor activity of bruceantin: an old drug with new promise.
Bruceantin was first isolated from Brucea antidysenterica, a tree used in Ethiopia for the treatment of cancer, and activity was observed against B16 melanoma, colon 38, and L1210 and P388 leukemia in mice. Phase I and II clinical trials were then initiated, but no objective tumor regressions were observed and clinical development was terminated. Recently, the activity of bruceantin has been studied with a number of leukemia, lymphoma, and myeloma cell lines. Cell differentiation was induced and c-MYC was down-regulated, suggesting a mechanistic correlation between c-MYC down-regulation and induction of cell differentiation or cell death. Treatment of HL-60 and RPMI 8226 cell lines induced apoptosis, and this involved the caspase and mitochondrial pathways. Moreover, an in vivo study using RPMI 8226 human-SCID xenografts demonstrated that bruceantin induced regression in early as well as advanced tumors, and these significant antitumor responses were facilitated in the absence of overt toxicity. Apoptosis was significantly elevated in tumors derived from animals treated with bruceantin. In sum, bruceantin interferes with the growth of leukemia, lymphoma, and myeloma cells in culture and xenograft models. Responses of this type suggest bruceantin should be reinvestigated for clinical efficacy against hematological malignancies.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Muriel
M
Cuendet
John M
JM
Pezzuto
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D032269:Brucea / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005002:Ethiopia; D006801:Humans; D051379:Mice; D010946:Plants, Medicinal / Q000737:chemistry*; D036702:Quassins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D036702:Quassins; C002550:bruceantin