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Saïd M Sebti

Publications and source records attributed to Saïd M Sebti.

27 records · Page 2Linked to original sources
PubMed2004

Disruption of the Rb--Raf-1 interaction inhibits tumor growth and angiogenesis.

The retinoblastoma tumor suppressor protein (Rb) plays a vital role in regulating mammalian cell cycle progression and inactivation of Rb is necessary for entry into S phase. Rb is inactivated by phosphorylation upon growth factor stimulation of quiescent cells, facilitating the transition from G(1) phase to S phase. Although the signaling events after growth factor stimulation have been well characterized, it is not yet clear how these signals contact the cell cycle machinery. We had found previously that growth factor stimulation of quiescent cells lead to the direct binding of Raf-1 kinase to Rb, leading to its inactivation. Here we show that the Rb-Raf-1 interaction occurs prior to the activation of cyclin and/or cyclin-dependent kinases and facilitates normal cell cycle progression. Raf-1-mediated inactivation of Rb is independent of the mitogen-activated protein kinase cascade, as well as cyclin-dependent kinases. Binding of Raf-1 seemed to correlate with the dissociation of the chromatin remodeling protein Brg1 from Rb. Disruption of the Rb-Raf-1 interaction by a nine-amino-acid peptide inhibits Rb phosphorylation, cell proliferation, and vascular endothelial growth factor-mediated capillary tubule formation. Delivery of this peptide by a carrier molecule led to a 79% reduction in tumor volume and a 57% reduction in microvessel formation in nude mice. It appears that Raf-1 links mitogenic signaling to Rb and that disruption of this interaction could aid in controlling proliferative disorders.

Animals↗
PubMed2003

Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice.

Treatment of H-Ras transgenic mice with the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-2154 results not only in halting the growth of aggressive breast tumors but actually in inducing the regression (54 +/- 3%) of all 19 tumors analyzed. The farnesyltransferase (FTase) inhibitor FTI-2148 induced an average of 87 +/- 3% regression in the 13 tumors analyzed. GGTase I, but not FTase, is inhibited in breast tumors after treatment with GGTI-2154, whereas in tumors from mice treated with FTI-2148, only FTase is inhibited. The processing of the geranylgeranylated proteins RhoA, Rap1, and R-Ras, but not the farnesylated proteins H-Ras and HDJ-2, is inhibited in tumors obtained from mice treated with GGTI-2154. GGTI-2154 and FTI-2148 suppress constitutively activated phospho-Erk1/2 and phospho-Akt, induce apoptosis, and induce differentiation toward ductolobular breast epithelium. The data demonstrate that geranylgeranylated proteins are critical in H-Ras oncogenesis in vivo and give strong support for GGTase I as a target for anticancer drug discovery.

Alkyl and Aryl Transferases↗
PubMed2003

Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting.

R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras,3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-alpha (TNF-alpha) levels by day 7 showed a trend toward correlation with response (P =.09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.

Aged↗
PubMed2003

Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice.

Constitutively activated, tyrosine-phosphorylated signal transducer and activator of transcription (STAT) 3 plays a pivotal role in human tumor malignancy. To discover disrupters of aberrant STAT3 signaling pathways as novel anticancer drugs, we developed a phosphotyrosine STAT3 cytoblot. Using this high throughput 96-well plate assay, we identified JSI-124 (cucurbitacin I) from the National Cancer Institute Diversity Set. JSI-124 suppressed the levels of phosphotyrosine STAT3 in v-Src-transformed NIH 3T3 cells and human cancer cells potently (IC(50) value of 500 nM in the human lung adenocarcinoma A549) and rapidly (complete inhibition within 1-2 h). The suppression of phosphotyrosine STAT3 levels resulted in the inhibition of STAT3 DNA binding and STAT3-mediated but not serum response element-mediated gene transcription. JSI-124 also decreased the levels of tyrosine-phosphorylated Janus kinase (JAK) but not those of Src. JSI-124 was highly selective for JAK/STAT3 and did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt, extracellular signal-regulated kinase 1/2, or c-Jun NH(2)-terminal kinase. Finally, JSI-124 (1 mg/kg/day) potently inhibited the growth in nude mice of A549 tumors, v-Src-transformed NIH 3T3 tumors, and the human breast carcinoma MDA-MB-468, all of which express high levels of constitutively activated STAT3, but it did not affect the growth of oncogenic Ras-transformed NIH 3T3 tumors that are STAT3 independent or of the human lung adenocarcinoma Calu-1, which has barely detectable levels of phosphotyrosine STAT3. JSI-124 also inhibited tumor growth and significantly increased survival of immunologically competent mice bearing murine melanoma with constitutively activated STAT3. These results give strong support for pharmacologically targeting the JAK/STAT3 signaling pathway for anticancer drug discovery.

3T3 Cells↗
PubMed2003

Blocked pathways: FTIs shut down oncogene signals.

Ras proteins play fundamental roles in cell signal transduction pathways that regulate cell growth, differentiation, proliferation, and survival. ras mutations are among the most frequently encountered genetic abnormalities in human cancers and play a key role in tumorigenesis. The enzymatic attachment of a 15- or 20-carbon moiety to the Ras protein through farnesylation or geranylgeranylation, respectively, is a required step in the proper localization and activation of Ras. Inhibition of the catalytic enzymes, farnesyl transferase and geranylgeranyl transferase, is a novel, mechanism-based, targeted approach to cancer therapy development. Geranylgeranyl transferase inhibitors suppress tumor growth by accumulating cells in the G(1)/S cell cycle phase. One mechanism by which farnesyl transferase inhibitors suppress tumor growth is by inhibiting bipolar spindle formation, thereby blocking progression from prophase to metaphase. Although the exact molecular target responsible for the antitumor activity of farnesyl transferase inhibitors is unclear, at least in some tumor cells, inhibition of phosphoinositide-3-OH kinase/Akt-mediated cell survival pathways may play a critical role. Identifying the farnesylated proteins that are targeted by farnesyl transferase inhibitors and the tumor molecular signatures that dictate which set of patients will respond to farnesyl transferase inhibitors are critical end points for future mechanistic studies.

Alkyl and Aryl Transferases↗
PubMed2003

The development of protein farnesyltransferase inhibitors as signaling-based anticancer agents.

The presence of mutated Ras in more that 30% of human cancers has spurred interest in the identification of molecules that can block its uncontrolled signaling function. A particular focus in recent years has been a key posttranslational modification of Ras that places a farnesyl group on a cysteine residue near the C-terminus of the protein. In this chapter we describe recent progress in the design of inhibitors for the enzyme that catalyzes this step, protein farnesyltransferase, and show their potential for blocking oncogenic cell growth.

Alkyl and Aryl Transferases↗
PubMed2003

Farnesyltransferase inhibitors as anticancer agents: current status.

Farnesyltransferase (FTase) is a major molecular target for the development of novel anticancer drugs that are designed to disrupt the aberrant signal transduction circuitry of tumor cells. The discovery more than a decade ago that farnesylation of Ras, one of the most prevalent oncoproteins in human cancers, is required for its cancer-causing activity was the initial stimulus to target FTase. However, it is now clear that yet to be identified farnesylated proteins other than Ras also play a pivotal role as targets for FTase inhibitors (FTIs). In this review, important mechanistic issues on the antiproliferative, pro-apoptotic and anti-angiogenic activities of FTIs, with an emphasis on potential FTI targets, will be discussed. Important clinical issues associated with translational aspects of hypotheses-driven clinical trials will also be discussed.

Alkyl and Aryl Transferases↗
PubMed2002

Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models.

Events that contribute to tumor formation include mutations in the ras gene and loss or inactivation of cell cycle inhibitors such as p21(Cip1) and p27(Kip1). In our previous publication, we showed that mice expressing the MMTV/v-Ha-ras transgene developed tumors earlier and at higher multiplicities in the absence than in the presence of p21(Cip1). To further evaluate the combinatorial role of genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we performed two companion studies. In the first study, wild type and p21(Cip1)-null mice were exposed to the chemical carcinogen, urethane. Similar to its effects in v-Ha-ras mice, loss of p21(Cip1) accelerated tumor onset and increased tumor multiplicity in urethane-treated mice. Lung tumors were the predominant tumor type in urethane-treated mice regardless of p21(Cip1) status. In the second study, tumor formation was monitored in v-Ha-ras mice expressing or lacking p27(Kip1). Unlike p21(Cip1), the absence of p27(Kip1) had no effect on the timing or multiplicity of tumor formation, which was largely restricted to mammary and salivary glands. However, once tumors appeared, they grew faster in p27(Kip1)-null mice than in p27(Kip1)-wild type mice. Increases in growth rate were particularly striking for salivary tumors in ras/p27(-/-) mice. Loss of p21(Cip1), on the other hand, had no effect on tumor growth rate in v-Ha-ras mice. Collectively, our data suggest that p21(Cip1) suppresses tumor formation elicited by multiple agents and that p21(Cip1) and p27(Kip1) suppress tumor formation in different ways.

Animals↗