Arglabin [1(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),11(13)-dien-6, 12-olide], a
sesquiterpene gamma-
lactone is isolated from Artemisia glabella, a species of wormwood endemic to the Karaganda region of Kazakstan. The compound has been modified to render it water-soluble through addition of a dimethylaminohydrochloride group to the C(13) carbohydride moiety to yield
Arglabin-DMA.
Arglabin-DMA is a registered antitumor substance in the Republic of Kazakstan. Previously, we have shown that this compound prevents protein farnesylation without altering geranylgeranylation. We now report that
Arglabin-DMA inhibits the incorporation of [(3)H]
farnesylpyrophosphate into human H-
ras protein by FTase with an IC(50) of no greater than 25 microM. Kinetic studies show that the phosphorylated form of this compound competitively inhibits the binding of
farnesyl diphosphate to FTase. This mechanism of action is different from other reported
peptidomimetic FTIs which lower the affinity of
ras protein to FTase. Our in vitro studies confirm that
Arglabin-DMA inhibits post-translational modification of
ras protein in cells.
Arglabin-DMA inhibits anchorage-dependent proliferation of NB cells (IC50=10 microg/ml) and inhibits anchorage-independent growth of NB and KNRK cells with about the same IC(50). Soft-
agar colony formation assay of H-ras and K-ras transformed cells show IC(50)s to be 2 and 5 microg/ml, respectively. In primary cultures of human
tumor cells,
Arglabin-DMA inhibits cell proliferation of a variety of
tumor types with IC(90)s in the range of 0.85 to 5.0 microg/ml. Because of these pharmacologic properties, we propose that
Arglabin-DMA is suitable for the treatment of ras related
malignancies.