A Farnesyltransferase Inhibitor Induces Tumor Regression in Transgenic Mice Harboring Multiple Oncogenic Mutations by Mediating Alterations in Both Cell Cycle Control and Apoptosis

Abstract

The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resultant tumor regression, MMTV-v-Ha-ras mice were interbred with p53 ؊/؊ mice. Tumors in ras/p53 ؊/؊ mice treated with L-744,832 regressed as efficiently as MMTV-v-Haras tumors, although this response was found to be mediated by both the induction of apoptosis and an increase in G 1 with a corresponding decrease in the S-phase fraction. MMTV-v-Ha-ras mice were also interbred with MMTV-c-myc mice to determine whether ras/myc tumors, which possess high levels of spontaneous apoptosis, have the potential to regress through a further increase in apoptosis levels. The ras/myc tumors were found to respond nearly as efficiently to L-744,832 treatment as the MMTV-v-Ha-ras tumors, although no induction of apoptosis was observed. Rather, the tumor regression in the ras/myc mice was found to be mediated by a large reduction in the S-phase fraction. In contrast, treatment of transgenic mice harboring an activated MMTVc-neu gene did not result in tumor regression. These results demonstrate that a farnesyltransferase inhibitor can induce regression of v-Ha-ras-bearing tumors by multiple mechanisms, including the activation of a suppressed apoptotic pathway, which is largely p53 independent, or by cell cycle alterations, depending upon the presence of various other oncogenic genetic alterations.

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

“…Finally, RhoB expression was found to be very low in 130 human cancer cell lines (Wang et al, 2003), giving further support to RhoB tumor suppressive activity. FTIs and GGTIs were shown to be potent inhibitors of cell proliferation and tumor growth in various animal models (Kohl et al, 1994;Nagasu et al, 1995;Barrington et al, 1998;Liu et al, 1998;Sun et al, 1998;Hunt et al, 2000). However, the mechanism by which this occurs is not known (Prendergast, 2001;Sebti and Der, 2003).…”

“…Because prenylation is required for Ras and Rho protein-mediated oncogenesis, metastasis and invasiveness, we and others have designed CAAX peptidomimetics that are potent and selective inhibitors of FTase (FTIs) and GGTase I (GGTIs), respectively, as potential anticancer drugs (Sebti and Hamilton, 2000). FTIs and GGTIs are potent inhibitors of Ras and Rho processing, respectively, and suppress the growth of murine and human tumors in various animal models (Kohl et al, 1994;Nagasu et al, 1995;Barrington et al, 1998;Liu et al, 1998;Sun et al, 1998;Hunt et al, 2000). Recent investigations into the biological mechanisms that underlie FTI anti-transforming effects have raised questions about their exact mode of action (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003).…”

Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer

“…In other systems, FTIs not only inhibited the oncogenic potential of v-Ha-Ras, in vitro and in vivo, but caused regression of established tumors. 41,45,46 Sensitivity to the FTI is therefore not dependent on the presence of Ras mutation or the unprocessing of wild type Ras in response to drug treatment. The data suggest that FTI affects the processing of other targets that are important for tumor growth or that our current model of Ras function is incomplete.…”

“…The original conception was that these drugs would ®nd their most appropriate use in tumors with mutations in the ras gene. Furthermore, despite the profound regressions produced by the drug in some animal models, 45,46 the drug usually results in stable disease in this type of system. This has led to the supposition that the drug will have to be given chronically in order to be of any use.…”

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

“…11 FTIs including SCH-66336 appear to promote tumor regression by multiple mechanisms, including apoptosis and cell cycle regulation. 6,7,12 MMPs, TIMPs and serine proteases of the plasminogen activation system, including uPA, uPAR, PAI-1 and plasmin, play pivotal roles in ECM remodeling during cancer invasion, metastasis and angiogenesis. [13][14][15][16][17] Components of the plasminogen activation system are regulated by Ras isoforms.…”