Effects of combretastatin A-4 prodrug against a panel of malignant human B-lymphoid cell lines.
Combretastatin A-4 (CA-4) is one of a family of compounds isolated from the South African willow tree Combretum caffrum. CA-4 was found to be active against murine melanoma and a variety of other human solid tumors. For the first time, we report the effect of CA-4 against a panel of malignant human B-lymphoid cell lines [early pre-B acute lymphoblastic leukemia (Reh), diffuse large cell lymphoma (WSU-DLCL2), chronic lymphocytic leukemia (WSU-CLL) and Waldenstrom's macroglobulinemia (WSU-WM)]. Our results indicate, using the prodrug form of CA-4, a concentration-dependent growth inhibition in all tested cell lines, although WSU-DLCL2 was more sensitive. Exposure to 4 nM CA-4 for 96 h induced 77% growth inhibition in Reh, 86% in WSU-CLL and 92% in WSU-WM. When used against the WSU-DLCL2 cell line, this same concentration of CA-4 was completely toxic. Morphological examination showed CA-4 induced the formation of giant, multinucleated cells, a phenomenon commonly found in mitotic catastrophe. Only minimal numbers of cells showing characteristics of apoptosis were detected. In WSU-DLCL2 cells, CA-4 (3 nM) induced the highest apoptosis (5%) after 48 h, while the percentage of dead cells was approximately 47%. Exposure of Reh, WSU-CLL, WSU-WM and WSU-DLCL2 cells for 24 h to 5 nM CA-4 induced 19, 28, 57 and 75% G2/M arrest, as determined by flow cytometry, respectively. Based on these preliminary studies, we believe that mitotic catastrophe is the predominant mechanism by which CA-4 induces cell death rather than apoptosis. Further studies to elucidate the mechanisms of CA-4 activity in vitro and in vivo are currently under investigation in our laboratory.
Division of Hematology and Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Ml 48201, USA.
S M
SM
Nabha
N R
NR
Wall
R M
RM
Mohammad
G R
GR
Pettit
A M
AM
Al-Katib
D017304:Annexin A5 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin