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A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated. It was found that the anti-proliferation activities of hybrids were better than that of FTS. Compound 10a displayed the strongest antitumor activities with IC50 values of 5.72–9.76 μmol/L and selectively inhibited tumor cell proliferation. In addition, 10a induced tumor cell apoptosis in a dose-dependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.

Novel farnesylthiosalicylic acid (FTA) derivatives 5a – m with different substituted 1,3,4-thiadiazoles were synthesized. Compounds 5b , 5c , 5e and 5f displayed anti-tumor activities superior to FTA in most cancer cells tested. Furthermore, 5e induced tumor cell apoptosis, which was accompanied by lower Bcl-2 expression, but with higher Bax and caspase 3 expression activities in cancer cells.

We hypothesized that Ras proximate 1 (Rap1) functions as an additional target for farnesylthiosalicylic acid (FTS) or its derivatives, and that the inhibition of Rap1 in lymphocytes by these agents may represent a method for treating inflammatory disorders. Indeed, we found that FTS-amide (FTS-A) was able to inhibit the elicitation phase of delayed cutaneous hypersensitivity in vivo. This effect was associated with the inhibition of Rap1 more than with the inhibition of Harvey rat sarcoma viral oncogene (Ras). Moreover, FTS-A inhibited Rap1 and contact sensitivity far better than FTS. We suggest that FTS-A may serve as a possible therapeutic tool in contact sensitivity in particular and T-cell-mediated inflammation in general.

The inhibition of human mesangial cell proliferation by S- trans, trans- farnesylthiosalicylic acid. Background Many of the proliferative cytokines implicated in human mesangial cell (HMC) proliferation signal through the superfamily of Ras GTPases. The Ras antagonist, S- trans, trans- farnesylthiosalicylic acid (FTS), was used to investigate the effects of the inhibition of Ras signaling on HMC proliferation. Methods Ras expression and membrane localization, MAPK, and Akt activation were analyzed by Western blotting. Ras activation was determined with a pull-down assay using the Ras-binding domain of Raf. HMC growth curves were assessed using the MTS assay of viable cell number, while DNA synthesis was measured with BrdU incorporation. Hoechst 33342 staining was used to determine apoptosis. Results FTS reduced the membrane localization of Ras in both serum and platelet-derived growth factor (PDGF). FTS (7.5-20 μmol/L) potently inhibited PDGF-induced HMC proliferation but had no effect on serum-induced proliferation. FTS (10-20 μmol/L) inhibited both Ras and phospho-MAPK activation by serum and PDGF. Furthermore, FTS (10-20 μmol/L) increased HMC apoptosis in the presence of PDGF but not in serum. Moreover, PDGF-stimulated activation of the survival protein Akt was inhibited by FTS. In contrast, serum-stimulated activation of Akt was unaffected by FTS. Conclusion FTS (5-20 μmol/L) inhibits PDGF-induced but not serum-induced HMC proliferation. FTS (10-20 μmol/L) also promotes HMC apoptosis in the presence of PDGF but not serum. These effects appear to be mediated by inhibitory effects on Ras-dependent signaling that occur as a result of the dislodgment of Ras from its membrane-anchorage sites by FTS. The selectivity of FTS toward PDGF-driven HMC proliferation suggests that FTS may be a valuable therapeutic in mesangioproliferative renal disease.

As RAS oncoproteins play a major role in human malignancy, inhibiting RAS function is a promising approach for developing anticancer therapies. Among these approaches are agents such as farnesyltransferase inhibitors (FTIs) and the nontoxic farnesylcysteine analogue farnesylthiosalicylic acid (FTS) that dislodges all RAS isoforms from the membrane, as well as methods to restore regulation of RAS-GTP levels and to alter the interaction of RAS-GTP with downstream targets.