A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1.
Extracts of Homalanthus nutans, a plant used in Samoan herbal medicine, exhibited potent activity in an in vitro, tetrazolium-based assay which detects the inhibition of the cytopathic effects of human immunodeficiency virus (HIV-1). The active constituent was identified as prostratin, a relatively polar 12-deoxyphorbol ester. Noncytotoxic concentrations of prostratin from greater than or equal to 0.1 to greater than 25 microM protected T-lymphoblastoid CEM-SS and C-8166 cells from the killing effects of HIV-1. Cytoprotective concentrations of prostratin greater than or equal to 1 microM essentially stopped virus reproduction in these cell lines, as well as in the human monocytic cell line U937 and in freshly isolated human monocyte/macrophage cultures. Prostratin bound to and activated protein kinase C in vitro in CEM-SS cells and elicited other biochemical effects typical of phorbol esters in C3H10T1/2 cells; however, the compound does not appear to be a tumor promoter. In skin of CD-1 mice, high doses of prostratin induced ornithine decarboxylase only to 25-30% of the levels induced by typical phorbol esters at doses 1/30 or less than that used for prostratin, produced kinetics of edema formation characteristic of the nonpromoting 12-deoxyphorbol 13-phenylacetate, and failed to induce the acute or chronic hyperplasias typically caused by tumor-promoting phorbols at doses of 1/100 or less than that used for prostratin.
Gustafson
K R
KR
Laboratory of Drug Discovery Research and Development, National Cancer Institute (NCI), Frederick Cancer Research & Development Center (FCRDC), Maryland 21702-1201.
Cardellina
J H
JH
McMahon
J B
JB
Gulakowski
R J
RJ
Ishitoya
J
J
Szallasi
Z
Z
Lewin
N E
NE
Blumberg
P M
PM
Weislow
O S
OS
Beutler
J A
JA
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004487:Edema / Q000139:chemically induced; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006965:Hyperplasia; D014905:Independent State of Samoa; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D010703:Phorbol Esters / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry*; D011493:Protein Kinase C / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects
D010703:Phorbol Esters; C070999:prostratin; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase