Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol

Semenov, Igor; Akyüz, Canan; Roginskaya, Vera; Chauhan, Dharminder; Corey, Seth J.

doi:10.1016/s0145-2126(01)00103-5

Cited by 43 publications

(30 citation statements)

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“…IL-6 binds to IL-6R/gp80, which induces phosphorylation and homodimerization of gp130 (Matsuda et al, 1994(Matsuda et al, , 1995Nishimoto et al, 1994;Taga et al, 1989;Kurth et al, 1999). Downstream of gp130 activation, IL-6 triggers Ras/Raf/MEK/p42/44 MAPK-mediated proliferation ; activates JAK/STAT3 signaling promoting MM cell survival by regulating Bcl-XL and/or Mcl-1 protein expression (Catlett-Falcone et al, 1999;Puthier et al, 1999a, b;Semenov et al, 2002); and activates PI3-K/Akt signaling, thereby promoting antiapoptosis and drug resistance in MM cells (Tu et al, 2000;Hideshima et al, 2001b). Importantly, these signaling cascades triggered by IL-6 may reduce the effectiveness of conventional chemotherapeutic agents against MM cells in BM milieu.…”

Section: Discussionmentioning

confidence: 99%

“…For example, IL-6 induces proliferation of MM cells via activation of the Ras/Raf/MEK/ERK signaling pathway , whereas IL-6-induced JAK/STAT3 signaling promotes MM cell survival by modulating Bcl-XL and/or Mcl-1 protein expression (Catlett-Falcone et al, 1999;Puthier et al, 1999a, b;Wei et al, 2001;Semenov et al, 2002). IL-6 also activates phosphatidylinositol-3 kinase (PI3-K) and downstream protein kinase Akt in MM cells (Tu et al, 2000;Hideshima et al, 2001b).…”

Section: Introductionmentioning

confidence: 99%

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Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma

et al. 2003

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Proteasome inhibitor PS-341 is one of the most promising novel agents against multiple myeloma (MM). We have previously shown that PS-341 inhibits IL-6 triggered phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 (also known as p42/44 mitogen-activated protein kinases) in MM cells. In this study, we further examined whether clinically achievable concentrations of PS-341 could inhibit IL-6 triggered signaling cascades in MM. We found that PS-341 inhibited not only ERK, but also signal transducers and activators of transcription (STAT) 3 as well as Akt phosphorylation. Since gp130 (CD130) dimerizes and is phosphorylated after IL-6 binding to gp80 (IL-6 receptor), we hypothesized that gp130 could be involved in PS-341-induced blockade of signaling cascades mediating MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment. In this study, we first demonstrate that PS-341 induces downregulation of gp130 in a time-and dose-dependent manner in vitro, prior to MM cell death. Conversely, downregulation of gp130 is completely abrogated by the pan-caspase inhibitor Z-VAD-FMK, suggesting that downregulation of gp130 is mediated via caspase activation. Z-VAD-FMK also abrogates the inhibitory effect of PS-341 on IL-6-triggered signaling cascades. Importantly, we demonstrate that phosphorylation of ERK, STAT3, and Akt in MM.1S cells induced by either exogenous IL-6 or by binding of MM cells to BM stromal cells is abrogated by PS-341. These studies, therefore, define another novel mechanism whereby PS-341 can overcome the growth and survival advantage in MM cells conferred by the BM milieu. Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma

et al. 2003

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“…FP binds to the CDK ATP binding pocket and potently inhibits cdk2, cdc2, and cdk4 at submicromolar concentrations, although at higher concentrations it inhibits other kinases, including protein kinase C, epidermal growth factor receptor, and extracellular regulated kinase 1 (Sedlacek et al, 2002). In preclinical studies, FP has been shown to induce apoptosis in lung cancer cells (Shapiro et al, 1999) and, at nanomolar concentrations, in malignant hematopoietic cells (Parker et al, 1998;Semenov et al, 2002). Administration of FP has been associated with G 2 M and G 1 S arrest, depending upon the model system (Carlson et al, 1996;Motwani et al, 1999), as well as down-regulation of cyclin D1 (Carlson et al, 1999).…”

Section: Waf1/cip1mentioning

confidence: 99%

Evidence of a Functional Role for p21/ Down-Regulation in Synergistic Antileukemic Interactions between the Histone Deacetylase Inhibitor Sodium Butyrate and Flavopiridol

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Almenara

et al. 2004

Molecular Pharmacology

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The functional significance of disruption of p21 WAF1/CIP1 induction by flavopiridol (FP) in human leukemia cells (Jurkat) exposed to the histone deacetylase (HDAC) inhibitor sodium butyrate (SB) was investigated. Coexposure of leukemic cells to FP blocked SB-mediated induction of p21 WAF1/CIP1 and resulted in a marked increase in mitochondrial injury, activation of procaspases-3 and -8, Bid cleavage, and PARP degradation. in Jurkat cells inducibly expressing p21WAF1/CIP1 under the control of a doxycycline-responsive promoter) partially but significantly reduced cytochrome c and apoptosis-inducing factor release, loss of mitochondrial membrane potential, caspase-3 and -8 activation, Bid cleavage, poly(ADP-ribose)polymerase (PARP) degradation, and apoptosis in response to SB/FP. Furthermore, increasing expression of p21 WAF1/CIP1 (i.e., by culturing cells in the presence of higher concentrations of doxycycline) rendered cells more resistant to SB/FP-mediated lethality. Enforced expression of p21 WAF1/CIP1 did not modify SB/FP-mediated JNK activation or generation of reactive oxygen species. Consistent with these results, Jurkat cells stably expressing a p21 WAF1/CIP1nuclear localization mutant (p21⌬NLS) were also resistant to SB/FP-mediated mitochondrial injury, activation of procaspases-3 and -8, PARP cleavage, and apoptosis. Finally, enforced expression of full-length or ectopic expression of ⌬NLS p21 WAF1/CIP1 increased the amount of p21 WAF1/CIP1 coimmunoprecipitating with procaspase-3. Together, these findings suggest that interruption of HDAC-mediated p21 WAF1/CIP1

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“…[3][4][5][6][7][8] One such agent is flavopiridol (FP) (L86-8275; NSC 649890), a cyclin-dependent kinase inhibitor (CDKI), which potently induces apoptosis in leukemia cells at very low concentrations (ie, nM). [9][10][11][12] In a recent study, it was reported that TNFa increased the lethality of FP in epithelial cancer cells and that a similar interaction was noted in the case of TRAIL. 13 However, it is presently unknown whether such an interaction might also occur in malignant hematopoietic cells, particularly those of leukemic origin.…”

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confidence: 99%

Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

et al. 2004

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Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x L , or a phosphorylation loop-deleted form of Bcl-2 (DBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/ FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FPmediated XIAP downregulation.

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Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol

Cited by 43 publications

References 20 publications

Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma

Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma

Evidence of a Functional Role for p21/ Down-Regulation in Synergistic Antileukemic Interactions between the Histone Deacetylase Inhibitor Sodium Butyrate and Flavopiridol

Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

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