Apoptotic and Cytostatic Farnesyltransferase Inhibitors Have Distinct Pharmacology and Efficacy Profiles in Tumor Models

Manne, Veeraswamy; Lee, Francis Y. F.; Bol, David K.; Gullo-Brown, Johnni; Fairchild, Craig R.; Lombardo, Louis J.; Smykla, Richard; Vite, Gregory D.; Wen, Mei-Li D.; Yu, Chiang; Wong, Tai W.; Hunt, John T.

doi:10.1158/0008-5472.can-03-3849

Cited by 20 publications

(15 citation statements)

References 36 publications

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“…28 However, despite extensive investigation, to date, the exact mode(s) of action of BMS-214662 has remained elusive. 23,26 Recent in vitro studies of BMS-214662 in B-cell chronic lymphocytic leukemia 40 and myeloma 41 have identified inhibition of Mcl-1 and Bax or Bak activation in association with apoptosis; however, this was not confirmed here for CML. What was very clear was that BMS-214662 caused cytotoxicity through apoptosis; this was confirmed using 3 alternative assays: expression of active caspase-3, TUNEL, and TMRE staining.…”

Section: Discussionmentioning

confidence: 70%

“…These compounds have similar inhibitory effects on FT with IC 50 s of 0.7 nM and 0.8 nM on the purified enzyme and in cells, for BMS-214662 and BMS-225975, respectively, but differ dramatically in their apoptotic and xenograft antitumor activity. 26 To determine whether the apoptotic effect of BMS-214662 in CML was due to more potent inhibition of FT in primary CML, we directly compared its activity with that of BMS-225975. The treatment conditions were: no drug control; BMS-214662; BMS-225975 250 nM; dasatinib; BMS-214662 ϩ dasatinib; BMS-225975 ϩ dasatinib.…”

Section: The Effect Of Bms-214662 On CML Stem/progenitor Cells Is Novmentioning

confidence: 99%

“…[19][20][21] However, the observed antitumor effects of FTIs are not solely the result of RAS inhibition 22,23 ; they may also act by inhibiting farnesylation of other proteins. 24,25 BMS-214662 is a cytotoxic FTI 26 that produces potent tumor regression and curative responses in human tumor xenografts and transgenic tumor models and differs from other, cytostatic FTIs, including lonafarnib and tipifarnib, which have noncurative activity. 22,27 In addition, BMS-214662 has been shown to preferentially kill nonproliferating cells 28 and has antileukemic activity in acute myeloid leukemia (AML).…”

Section: Introductionmentioning

confidence: 99%

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BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Copland

Pellicano

Richmond

et al. 2008

Blood

112

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IntroductionChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder originating in a hematopoietic stem cell. It is characterized by the Philadelphia (Ph) chromosome, 1 arising from a reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in fusion of the BCR gene on chromosome 22 with the ABL oncogene on chromosome 9, with expression of its fusion gene product, BCR-ABL, a constitutively active tyrosine kinase. 2 The deregulated BCR-ABL tyrosine kinase activity is essential for its transforming ability, 3 resulting in phosphorylation of cellular substrates and activation of signal transduction pathways, including the RAS-ERK cascade, JAK-STAT, PI3-kinase, c-Myc, c-CBL, and CrKL, affecting cell growth, stromal interaction, and apoptosis. [4][5][6] Imatinib mesylate (IM; Novartis Pharma, Basel, Switzerland) is a tyrosine kinase inhibitor (TKI) active against ABL, c-KIT, and PDGFR, acting by competitive inhibition of adenosine triphosphate binding to the tyrosine kinase. 7 Despite an impressive rate of durable complete cytogenetic response in chronic phase CML patients treated with IM, 8 only a minority of patients achieve complete molecular remission. 9 At least 2 mechanisms of resistance appear to account for residual disease in these patients: the innate insensitivity of primitive quiescent CML stem/progenitor cells, which greatly overexpress BCR-ABL, to IM 10,11 and BCR-ABL kinase mutations, 12 which are present before IM therapy in a subgroup of patients and result in IM resistance. 13,14 However, there is currently no direct evidence that these resistance mechanisms, observed in vitro, are responsible for residual disease in IM-treated patients.Two main strategies to overcome IM resistance have emerged. These are the development of second generation TKIs 15,16 and the use of IM in drug combinations. 17 Dasatinib (Sprycel, formerly BMS-354825; Bristol-Myers Squibb, Stamford, CT) is an oral, multitargeted inhibitor of BCR-ABL and SRC kinases, with greatly improved potency against wild-type (WT) BCR-ABL, capable of binding all known BCR-ABL kinase mutants resistant to IM except T315I. 15 In our previous work, although dasatinib induced durable inhibition of BCR-ABL in primitive progenitor cells from CML patients compared with either IM or nilotinib, which were ineffective, 11,18 none of these TKIs targeted the most primitive, quiescent CML stem/progenitor cells. Of a wide range of rational drug combinations, 17 the only agent to synergize with IM against these cells was the cytostatic farnesyltransferase inhibitor (FTI) lonafarnib (Schering-Plough). 17 FTIs inhibit oncogenic RAS and have entered clinical trials in solid tumors and acute leukemias. [19][20][21] However, the observed antitumor effects of FTIs are not solely the result of RAS inhibition 22,23 ; they may also act by inhibiting farnesylation of other proteins. 24,25 BMS-214662 is a cytotoxic FTI 26 that produces potent tumor regression and curative responses in human tumor xenografts and transgenic tumor mode...

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Section: Discussionmentioning

confidence: 70%

Section: The Effect Of Bms-214662 On CML Stem/progenitor Cells Is Novmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Copland

Pellicano

Richmond

et al. 2008

Blood

112

View full text Add to dashboard Cite

show abstract

“…BMS-214662, the only active drug among the five assayed, is the most potent apoptotic FTI known and exhibits curative responses in mice bearing a variety of staged human tumor xenografts such as HCT-116 human colon tumor (47,48). A recent study (48) showed that BMS-214662 and BMS-225975, two tetrahydrobenzodiazepine-based FTIs that have nearly identical structures and very similar pharmacologic profiles associated with FTase inhibition, displayed different apoptotic property. BMS-225975 did not cause tumor regression and at best caused partial tumor-growth inhibition in staged HCT-116 human colon tumor xenografts.…”

Section: Ftis In Mesothelioma 2032mentioning

confidence: 99%

Farnesyltransferase Inhibitors and Human Malignant Pleural Mesothelioma: A First-Step Comparative Translational Study

Cesario

Catassi

Festi

et al. 2005

Clinical Cancer Research

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“…Clinical activities have been observed with hematopoietic malignancies and breast cancer (1 -4). One of the recent advances in the development of FTIs is the generation of a novel, highly specific FTI compound BMS-225975 (5). This compound is a derivative of a clinical compound BMS-214662 (6, 7), a tetrahydrobenzodiazepine FTI identified through a screen for a thiol surrogate which could function as a zinc ligand.…”

Section: Introductionmentioning

confidence: 99%

Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments inTsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways

Gau

Kato-Stankiewicz

Chen

et al. 2005

Molecular Cancer Therapeutics

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Farnesyltransferase inhibitors (FTI) have been developed as anticancer drugs and are currently being evaluated in clinical trials. In this study, we have examined the effects of FTIs on Tsc-null cells to gain insight into their effects on farnesylated Rheb GTPase. This protein is involved in the activation of mTOR/S6K signaling and is down-regulated by the Tsc1/Tsc2 complex. Both Tsc1 À/À and Tsc2 À/À mouse embryonic fibroblasts exhibit constitutive activation of S6K and grow in the absence of serum. Two different FTI compounds, the clinical compound BMS-214662 and the newly described BMS-225975, inhibit the constitutive activation of mTOR/S6K signaling and block serum-free growth of the Tsc-null mouse embryonic fibroblasts. We have also found that Tsc-null mouse embryonic fibroblasts grow under anchorage-independent conditions and that both FTI compounds inhibit this soft agar growth. These FTI effects are similar to those observed with rapamycin. Another interesting phenotype of Tsc-null mouse embryonic fibroblasts is that they are round and contain actin filaments predominantly at the cell periphery. The addition of FTIs, but not rapamycin, led to the reappearance of intracellular actin filaments and reduction of peripheral actin filaments. The ability of FTI to rearrange actin filaments seems to be largely mediated by the inhibition of Rheb protein, as induction of intracellular actin filaments by FTI was much less efficient in Tsc2-null cells expressing Rheb (M184L), a geranylgeranylated mutant Rheb that can bypass farnesylation. These results reveal that FTIs inhibit Rheb, causing two different effects in Tsc-deficient cells, one on growth and the other on actin filament distribution. [Mol Cancer Ther 2005;4(6):918 -26]

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Apoptotic and Cytostatic Farnesyltransferase Inhibitors Have Distinct Pharmacology and Efficacy Profiles in Tumor Models

Cited by 20 publications

References 36 publications

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Farnesyltransferase Inhibitors and Human Malignant Pleural Mesothelioma: A First-Step Comparative Translational Study

Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments inTsc-deficient cells via inhibition of both rapamycin-sensitive and -insensitive pathways

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