Arglabin-DMA, a plant derived sesquiterpene, inhibits farnesyltransferase

Arglabin [1(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),11(13)-dien-6, 12-olid e], a sesquiterpene gamma -lactone is isolated from Artemisia glabella, a s pecies of wormwood endemic to the Karaganda region of Kazakstan. The compou nd has been modified to render it water-soluble through addition of a dimet hylaminohydrochloride group to the C-13 carbohydride moiety to yield Arglab in-DMA. Arglabin-DMA is a registered antitumor substance in the Republic of Kazakstan. Previously, we have shown that this compound prevents protein f arnesylation without altering geranylgeranylation. We now report that Argla bin-DMA inhibits the incorporation of [H-3]farnesylpyrophosphate into human H-ras protein by FTase with an IC50 of no greater than 25 muM. Kinetic stu dies show that the phosphorylated form of this compound competitively inhib its the binding of farnesyl diphosphate to FTase. This mechanism of action is different from other reported peptidomimetic FTIs which lower the affini ty 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 NE cells (IC50 = 10 mug/m l) and inhibits anchorage-independent growth of NE and KNRK cells with abou t the same IC50. Soft-agar colony formation assay of H-ras and K-ras transf ormed cells show IC(50)s to be 2 and 5 mug/ml, respectively. In primary cul tures of human tumor cells, Arglabin-DMA inhibits cell proliferation df a v ariety of tumor types with IC(90)s in the range of 0.85 to 5.0 mug/ml. Beca use of these pharmacologic properties, we propose that Arglabin-DMA is suit able for the treatment of ras related malignances.