The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells

Bolick, Sophia C.E.; Landowski, Terry H.; Boulware, David; Oshiro, Marc M.; Ohkanda, Junko; Hamilton, Andrew D.; Sebti, Saı̈d M.; Dalton, William S.

doi:10.1038/sj.leu.2402832

Cited by 65 publications

(40 citation statements)

References 15 publications

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“…RPMI 8226, NCI-H929, and U266 are resistant to glucocorticoids and/or DNA-damaging agents (see for example refs. 43,44). Resistance towards conventional anticancer drugs frequently appears de novo during the treatment of multiple myeloma disease.…”

Section: Resultsmentioning

confidence: 99%

4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members

Gauduchon

Gouilleux

Maillard

et al. 2005

Clinical Cancer Research

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Purpose: Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies. Our approach was to analyze the in vitro effects of a selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT), on six multiple myeloma cell lines. Experimental Design: Cultured multiple myeloma cells were treated with various 4-OHT concentrations and the cellular response was studied: cell proliferation, cell viability, induction of apoptosis, caspase activities, and expression of signaling proteins. Results: We found that pharmacologic concentrations of 4-OHT inhibit cell proliferation (4 of 6 cell lines). This inhibition is achieved by two independent events: a block at the G1 phase of the cell cycle and the induction of apoptotic death. The cellular response to 4-OHT depends on the presence of functional estrogen receptors. 4-OHT treatment activates an intrinsic mitochondrial caspase-9-dependent pathway but not the Fas/FasL death pathway. Signaling pathways known to be involved in the survival and/or proliferation of multiple myeloma cells are not affected by 4-OHT treatment. 4-OHT-induced G1 arrest is accompanied by the up-regulation of the cell cycle inhibitor p27Kip1 and the down-regulation of c-Myc. Among the Bcl-2 family members tested, the proapoptotic BimS protein is induced whereas the antiapoptotic protein Mcl-1 is decreased. Conclusions: Although the effects of 4-OHT are observed at micromolar concentrations, cellular mechanisms responsible for G1 arrest, as well as apoptosis induction, are similar to those observed in breast cancer cells. Our data support the concept that 4-OHT may represent an alternative approach to inhibit proliferation and induce apoptosis of multiple myeloma cells.

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Section: Resultsmentioning

confidence: 99%

4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members

Gauduchon

Gouilleux

Maillard

et al. 2005

Clinical Cancer Research

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“…which are also subject to farnesylation (56). Analogously, in multiple myeloma, whereas the status of Ras may influence the response of cells to farnesyltransferase inhibitors, an absolute correlation between these events has not been observed (11), suggesting that other factors are in all likelihood involved in lethality. It should be noted that regardless of direct effects on Ras farnesylation, coadministration of L744832 with UCN-01 was associated with a clear diminution in activation of ERK as well as Akt and several of its downstream targets, including GSK-3 and p70S6K.…”

Section: Discussionmentioning

confidence: 99%

“…However, the activity of farnesyltransferase inhibitors against tumor cells expressing wild-type Ras, or bearing Ras mutations that do not require farnesylation for activation, suggests the presence of targets other than farnesyltransferase (10). Several groups have shown that farnesyltransferase inhibitors induce apoptosis in multiple myeloma cells through a process influenced by the presence and type of Ras mutation (11,12).…”

mentioning

confidence: 99%

The Farnesyltransferase Inhibitor L744832 Potentiates UCN-01–Induced Apoptosis in Human Multiple Myeloma Cells

Pei

Dai

Rahmani

et al. 2005

Clinical Cancer Research

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Purpose: The purpose of this study was to characterize interactions between the farnesyltransferase inhibitor L744832 and the checkpoint abrogator UCN-01 in drug-sensitive and drug-resistant human myeloma cell lines and primary CD138 + multiple myeloma cells. Experimental Design: Wild-type and drug-resistant myeloma cell lines were exposed to UCN-01 FL744832 for 24 hours, after which mitochondrial injury, caspase activation, apoptosis, and various perturbations in signaling and survival pathways were monitored. Results: Simultaneous exposure of myeloma cells to marginally toxic concentrations of L744832 and UCN-01resulted in a synergistic induction of mitochondrial damage, caspase activation, and apoptosis, associated with activation of p34 cdc2 and c-Jun-NH 2 -kinase and inactivation of extracellular signal-regulated kinase, Akt, GSK-3, p70 S6K , and signal transducers and activators of transcription 3 (STAT3). Enhanced lethality for the combination was also observed in primary CD138 + myeloma cells, but not in their CD138 À counterparts. L744832/UCN-01^mediated lethality was not attenuated by conventional resistance mechanisms to cytotoxic drugs (e.g., melphalan or dexamethasone), addition of exogenous interleukin-6 or insulin-like growth factor-I, or the presence of stromal cells. In contrast, enforced activation of STAT3 significantly protected myeloma cells from L744832/UCN-01^induced apoptosis. Conclusions: Coadministration of the farnesyltransferase inhibitor L744832 promotes UCN01^induced apoptosis in human multiple myeloma cells through a process that may involve perturbations in various survival signaling pathways, including extracellular signal-regulated kinase, Akt, and STAT3, and through a process capable of circumventing conventional modes of myeloma cell resistance, including growth factor^and stromal cell^related mechanisms. They also raise the possibility that combined treatment with farnesyltransferase inhibitors and UCN-01 could represent a novel therapeutic strategy in multiple myeloma.

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“…The use of an FTI inhibits the growth and induces apoptosis in drug resistant myeloma tumor cells. 29 The sequence of bortezomib followed by an FTI (lonafarnib) induces synergistic cell death in both MM cell lines and patient samples. These preclinical studies suggest that FTIs may represent new therapeutic agents for the treatment of refractory MM.…”

Section: Discussionmentioning

confidence: 99%

Multiple myeloma: Implementing signaling pathways and molecular biology in clinical trials

Bazzi

Badros²

2010

Cancer Biology & Therapy

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The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells

Cited by 65 publications

References 15 publications

4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members

4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members

The Farnesyltransferase Inhibitor L744832 Potentiates UCN-01–Induced Apoptosis in Human Multiple Myeloma Cells

Multiple myeloma: Implementing signaling pathways and molecular biology in clinical trials

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