Sapphyrins induce apoptosis in hematopoietic tumor-derived cell lines and show in vivo antitumor activity.
Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins. In the present study, the activity of sapphyrins as anticancer agents in hematopoietic-derived tumor cells was explored. It was found that a dihydroxylated water-soluble sapphyrin derivative (PCI-2000) is a potent inducer of apoptosis in a wide variety of tumor cell lines including lymphoma (Ramos, DHL-4, and HF-1), leukemia (Jurkat and HL-60), and myeloma (8226/S, 1-310, C2E3, and 1-414). PCI-2000 triggers an apoptotic pathway in these tumor cells as shown by release of cytochrome c from mitochondria; activation of caspases 9, 8, and 3; cleavage of the caspase substrate poly(ADP-ribose) polymerase; and Annexin V binding. Apoptosis can be partially inhibited by overexpression of the antiapoptotic protein Bcl-2 or treatment with benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone, a cell-permeable caspase inhibitor. Both PCI-2000 and PCI-2010, a tetrahydroxy bis-carbamate derivative of PCI-2000, result in increased levels of phosphorylated p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase phosphorylation resulted in a synergistic increase of PCI-2000 cytotoxicity. PCI-2010 showed less toxicity in mice than PCI-2000 and was active in slowing the growth of Ramos and HL-60 tumor xenografts in nude mice. These results provide preclinical rationale for the further study of sapphyrins for potential use in the treatment of hematopoietic-derived tumors.
Naumovski
Louie
L
Pharmacyclics, Inc., Sunnyvale, CA 94085, USA. Inaumovski@pcyc.com
Ramos
Jason
J
Sirisawad
Mint
M
Chen
Jun
J
Thiemann
Patti
P
Lecane
Philip
P
Magda
Darren
D
Wang
Zhong
Z
Cortez
Cecilia
C
Boswell
Garry
G
Gyu Cho
Dong
D
Sessler
Jonathan
J
Miller
Richard
R
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C504033:PCI 2000; C504034:PCI 2010; D011166:Porphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; C440448:sapphyrin; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases