ライフサイエンスコーパス: PS-341

1 nfer sensitivity to bortezomib (Velcade (R); PS-341).

2 vity to proteasome inhibition by bortezomib (PS-341).

3 e the first dose or after the third cycle of PS-341.

4 caspase activation and apoptosis induced by PS-341.

5 ers PS-341-sensitive DHL6 cells resistant to PS-341.

6 MM cells to BM stromal cells is abrogated by PS-341.

7 t account for all of the anti-MM activity of PS-341.

8 per meter squared, and the absolute dose of PS-341.

9 cellular impact of the proteasome inhibitor PS-341.

10 sensitized to TRAIL by either Dox, SN50, or PS-341.

11 to further examine the antitumor activity of PS-341.

12 levels were actually elevated on exposure to PS-341.

13 at was induced by proteasome inhibition with PS-341.

14 isease in a phase II study do not respond to PS-341.

15 rategy to enhance the anticancer efficacy of PS-341.

16 r CT-32615 could also overcome resistance to PS-341.

17 were assigned to treatment groups receiving PS-341 0.05 mg/kg (n = 13), 0.1 mg/kg (n = 15), 0.5 mg/k

18 th combination therapy comprising 2 doses of PS-341 (0.5 mg/kg), 1 day prior to and 1 day following 1

19 vals of mice treated with saline, 2 doses of PS-341 (0.5 mg/kg), or a single nonmyeloablative dose of

20 PS-341 1.5 mg/m(2) was administered intravenously twice

21 ted with the dipeptide boronic acid analogue PS-341 (1 microM) prior to exposure to SN-38, the active

22 PS-341 (10(-7) M, 24 h) decreased nuclear NF-kappaB leve

23 f the cells became apoptotic when exposed to PS-341 (10(-7) M, 24-48 h) as shown by Annexin V analysi

24 Bortezomib (PS-341), a selective inhibitor of proteasome, induces ap

25 Bortezomib (PS-341), a selective inhibitor of proteasomes, induces a

26 Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antit

27 of UPase by TNF-alpha could be suppressed by PS-341, a NF-kappaB inhibitor.

28 PS-341, a novel boronic acid dipeptide that inhibits 26S

29 We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome i

30 PS-341, a potent, competitive inhibitor of the proteasom

31 We demonstrate that PS-341, a small molecule inhibitor of the proteasome, ma

32 Moreover, PS-341 abolished cell adhesion-mediated drug resistance.

33 Importantly, the proteasome inhibitor PS-341 abrogated TNFalpha-induced NF-kappaB activation,

34 PS-341 activated JNK/c-Jun signaling in GBM cells, and t

35 PS-341 activated the BH3-only proteins Bik and Bim and d

36 In Tax transgenic mice, PS-341 administered thrice weekly inhibited tumor-associ

37 For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor k

38 bition (64-75%) compared with treatment with PS-341 alone (20-30%) or SN-38 alone (24-47%; P < 0.002)

39 The results indicate that PS-341 alone is an effective therapy for patients with M

40 PS-341 also inhibits human MM cell growth and prolongs s

41 PS-341 also inhibits the paracrine growth of human MM ce

42 Furthermore, PS-341 also targeted the corresponding catalytic subunit

43 PS-341 (also called Bortezomib or Velcade) is the first

44 PS-341, also known as Velcade or Bortezomib, represents

45 and proteomic analysis, we demonstrate that PS-341, among its other proapoptotic effects, down-regul

46 the ubiquitin proteasome pathway, including PS-341, an anticancer drug in clinical use.

47 tic killing of myeloma cells exposed to both PS-341 and 153-Sm-EDTMP.

48 e growth and survival of MCL cells, and that PS-341 and BAY 11 may be useful therapeutic agents for M

49 studies are underway to test the efficacy of PS-341 and chemotherapeutic agents as combination therap

50 These studies identify molecular targets of PS-341 and provide the rationale for the development of

51 olecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of P

52 HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of th

53 mor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the

54 cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to prefer

55 In overnight assays, combinations of PS-341 and TRAIL were much more effective than either ag

56 apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are s

57 Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM

58 le control, PS-341, Zol, or a combination of PS-341 and Zol.

59 appaB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (

60 with bortezomib (VELCADE, formerly known as PS-341) and other proteasome inhibitors indicate that ca

61 y approved proteasome inhibitor, bortezomib (PS-341), and compare it with other inhibitors, taking it

62 ry derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act directly on multiple myeloma (

63 Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)-kappaB

64 Geldanamycin, PS-341, and TRAIL triple combination may be a novel ther

65 In this study, we show that PS-341 at concentrations that effectively inhibited the

66 domide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-b

67 Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a

68 The proteasome inhibitor PS-341 (bortezomib or Velcade), an approved drug for tre

69 sful clinical trials of proteasome inhibitor PS-341 (bortezomib) in solid tumors led to the invention

70 PS-341 (bortezomib) is a potent and reversible proteosom

71 Although PS-341 (bortezomib) is a promising agent to improve mult

72 PS-341 (bortezomib, Velcadetrade mark) is a promising no

73 These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellula

74 induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin.

75 ish NF-kappaB DNA binding activity; however, PS-341, but not ectopic expression of IkappaBalphaM, sen

76 Recent in vitro data also demonstrate that PS-341 can markedly sensitize chemotherapy-resistant MM

77 fore, define another novel mechanism whereby PS-341 can overcome the growth and survival advantage in

78 some inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vit

79 Moreover, exposure of such cells to PS-341 caused them to accumulate in the G2-M phase of th

80 Both IkappaBalphaM and PS-341 completely abolish NF-kappaB DNA binding activity

81 ther clinically achievable concentrations of PS-341 could inhibit IL-6 triggered signaling cascades i

82 Although PS-341 could inhibit NF-kappaB activation, the inhibitio

83 Consistently, PS-341 could not induce the ER stress-ROS in PS-341-resi

84 nhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27.

85 We found that PS-341 decreased cell viability, increased apoptosis, an

86 We report that the proteasome inhibitor PS-341 decreased NF-kappaB DNA binding activity by preve

87 urther studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic pro

88 activity of Bortezomib/Proteasome inhibitor PS-341, dexamethasone (Dex) and 2-Methoxyestradiol (2ME2

89 we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apopt

90 Significantly, PS-341 displayed similar effects in vivo.

91 PS-341 disrupted lysosomes with redistribution of cathep

92 induced by PS-341 treatment, suggesting that PS-341 does not trigger a stress response in DHL-4 cells

93 PS-341 downregulated the expression of Bcl-2 and Bcl-xl

94 In vitro, PS-341 elicits proteasome inhibition, leading to an incr

95 Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing li

96 ty of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2

97 Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing th

98 SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and pati

99 One proposed mechanism by which PS-341 exerts its anticancer effect is inactivation of n

100 As a result, PS-341 facilitated p65 nuclear translocation and increas

101 d the JNK signaling to reverse partially the PS-341 growth inhibition.

102 Oral administration of PS-341 had anti-inflammatory effects in a model of Strep

103 Importantly, PS-341 has achieved remarkable clinical responses in pat

104 PS-341 has marked clinical activity even in the setting

105 In summary, PS-341 has profound effects on growth and apoptosis of G

106 These studies therefore demonstrate that PS-341 has significant in vivo antimyeloma activity at d

107 e National Cancer Institute in vitro screen, PS-341 has substantial cytotoxicity against a broad rang

108 erized molecular mechanisms of resistance to PS-341 in DHL-4 cells.

109 strategy restores the apoptotic response to PS-341 in DHL4 cells; conversely, ectopic expression of

110 cking for clinically significant activity of PS-341 in metastatic renal cell cancer.

111 on, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer.

112 and composition in myeloma cells exposed to PS-341 in the presence or absence of cytokines present i

113 the rationale for future clinical trials of PS-341, in combination with conventional and novel thera

114 ses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokale

115 Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles.

116 In agreement, PS-341 increased calpain activity.

117 PD studies revealed PS-341 induced 20S proteasome inhibition in a time-depen

118 PS-341 induced a dose-dependent apoptosis in association

119 s harvested from treated animals showed that PS-341 induced apoptosis and decreased angiogenesis in v

120 In the present study, we show that PS-341 induced caspase-8-dependent apoptosis, cooperated

121 ches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and rea

122 s the important role of DR5 up-regulation in PS-341-induced apoptosis and enhancement of TRAIL-induce

123 , indicating that DR5 up-regulation mediates PS-341-induced apoptosis and enhancement of TRAIL-induce

124 c-FLIP with c-FLIP siRNA sensitized cells to PS-341-induced apoptosis, suggesting that c-FLIP elevati

125 ng that c-FLIP elevation protects cells from PS-341-induced apoptosis.

126 apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis.

127 However, PS-341-induced apoptotic cascade(s) are not yet fully de

128 hypothesized that gp130 could be involved in PS-341-induced blockade of signaling cascades mediating

129 PS-341-induced caspase-2 activation was attenuated by a

130 ive Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3

131 PS-341-induced cytochrome c release and phosphatidylseri

132 Blockage of PS-341-induced DR5 up-regulation using DR5 small interfe

133 novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mito

134 Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M-phase cells, associated

135 (ii) Two representative PS-341-induced miRs: miR-30b-5p and miR-30c-5p are found

136 Caspase-2 activation regulates PS-341-induced mitochondrial depolarization and apoptosi

137 PS-341-induced mitochondrial depolarization was attenuat

138 Inhibition of JNK activity abrogates PS-341-induced MM cell death.

139 tional eIF2alpha played an essential role in PS-341-induced Noxa expression.

140 These data together indicate that PS-341 induces a calpain-mediated IkappaB(alpha) degrada

141 Preclinical studies have shown that PS-341 induces apoptosis and enhances tumor necrosis fac

142 PS-341 induces apoptosis and has shown broad antitumor a

143 ave recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myel

144 Treatment with PS-341 induces apoptosis in SUDHL6 (DHL6), but not SUDHL

145 In this study, we first demonstrate that PS-341 induces downregulation of gp130 in a time- and do

146 Taken together, PS-341 induces lysosomal cathepsin B redistribution upst

147 one, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-kappaB activity as part of their div

148 Pretreatment with PS-341 inhibited activation of NF-kappaB induced by SN-3

149 We found that PS-341 inhibited not only ERK, but also signal transduce

150 ting the expression of apoptosis inhibitors, PS-341 inhibits genotoxic stress response pathways and t

151 shown recently that the proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes

152 The proteasome inhibitor PS-341 inhibits IkappaB degradation, prevents NF-kappaB

153 We have previously shown that PS-341 inhibits IL-6 triggered phosphorylation of extrac

154 The proteasome inhibitor PS-341 inhibits nuclear factor-kappaB (NF-kappaB) activa

155 of PS-341, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear.

156 Direct injection of PS-341 into the tumor also caused a substantial (70%) de

157 The proteasome inhibitor PS-341 is a new specifically targeted proapoptotic thera

158 PS-341 is a potent, selective in vivo radiosensitizer th

159 When PS-341 is combined with TRAIL, the levels of activated c

160 PS-341 is currently under clinical evaluation for advanc

161 Proteasome inhibitor PS-341 is one of the most promising novel agents against

162 Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a

163 Bortezomib (PS-341) is a novel antineoplastic agent that is well tol

164 Bortezomib (Velcade; previously called PS-341) is a potent and specific inhibitor of the 26S pr

165 Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clini

166 e potent and selective proteasome inhibitor, PS-341, is particularly promising from a therapeutic per

167 PS-341 markedly inhibited proliferation of GBM cell line

168 and apoptosis of GBM cells, suggesting that PS-341 may be an effective therapy for patients with gli

169 dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistan

170 SCC cells, providing novel insights into the PS-341-mediated antitumor activity.

171 all interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells.

172 ere demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM

173 he abolishment of the prosurvival NF-kappaB, PS-341 might directly induce apoptosis by activating pro

174 olated from a patient who had relapsed after PS-341 monotherapy.

175 These data illustrate that PS-341 not only reaches its biological target but has a

176 Moreover, IkappaB(alpha) degradation by PS-341 occurred early before induction of apoptosis and

177 ells in culture revealed that the effects of PS-341 on cell growth largely correlated with inhibition

178 -FMK also abrogates the inhibitory effect of PS-341 on IL-6-triggered signaling cascades.

179 We studied the effect of PS-341 on lysosomal and mitochondrial permeabilization,

180 However, the effect of PS-341 on the growth of tumors in Tax transgenic mice re

181 tutive NF-kappaB by the proteasome inhibitor PS-341 or a specific pIkappaBalpha inhibitor, BAY 11-708

182 ess sensitive to apoptosis induced by either PS-341 or its combination with TRAIL, indicating that DR

183 we found that long-term incubation with PIs (PS-341 or MG132) increased NF-kappaB-regulated gene expr

184 versus those treated with the combination of PS-341 plus 153-Sm-EDTMP.

185 ic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-

186 Here we found that PS-341 potently activated the caspase cascade and induce

187 dy, we found that subtoxic concentrations of PS-341 potently sensitized MM cell lines and patient cel

188 therapeutic proteasome inhibitor bortezomib (PS-341), proteasome function in tumor xenografts was blo

189 poptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synerg

190 However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits MM cell

191 some inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration a

192 PS-341 reduced PTHrP and MIP-1 alpha expression in tumor

193 ochemical target and that inhibitors such as PS-341 represent a unique class of antitumor agents.

194 work for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.

195 atment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcome

196 ance, and that inhibition of Hsp27 overcomes PS-341 resistance.

197 rovide the first evidence that Hsp27 confers PS-341 resistance.

198 ugmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells.

199 nhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework fo

200 PS-341 could not induce the ER stress-ROS in PS-341-resistant HNSCC cells.

201 y, GCS-100 decreases viability of bortezomib/PS-341-resistant multiple myeloma patient cells.

202 Annexin V staining indicated that PS-341 response in vivo correlated with sensitivity to a

203 es also revealed that i.v. administration of PS-341 resulted in a rapid and widespread distribution o

204 show that inhibition of this target site by PS-341 results in reduced tumor growth in murine tumor m

205 ously reported that the proteasome inhibitor PS-341 selectively sensitizes myeloma cells to the letha

206 ctopic expression of wild-type Hsp27 renders PS-341-sensitive DHL6 cells resistant to PS-341.

207 ers resistance to Taxol-induced apoptosis in PS-341 sensitized cells.

208 The tumor tissues treated with PS-341 show no consistent inhibition of NFkappaB activat

209 PS-341 showed activity against refractory multiple myelo

210 tment with the licensed proteasome inhibitor PS-341 slows the growth of ES-2 ovarian carcinoma xenogr

211 PS-341 stimulated the phosphorylation of PERK and the un

212 Geldanamyin and PS-341 synergistically block NFkappaB activation, suppre

213 These data suggest that PS-341 targets both normal and immunoproteasome species

214 proteasome catalytic subunits, we show that PS-341 targets the beta5 and beta1 subunits in a concent

215 Here we report that the proteasome inhibitor PS-341, the representative of a new class of chemotherap

216 thesized that NF-kappaB is a major target of PS-341, the underlying mechanism by which PS-341 inhibit

217 L), dexamethasone, and proteasome inhibitor (PS-341) therapy.

218 After PS-341, there was a decrease in mean whole blood SpA and

219 hance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.

220 eptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical

221 ide the framework for clinical evaluation of PS-341 to improve outcome for patients with this univers

222 DR5 induction correlated with the ability of PS-341 to induce apoptosis.

223 Following weekly i.v. treatment of PS-341 to mice bearing the PC-3 tumor, a significant dec

224 her supporting the early clinical promise of PS-341 to overcome drug resistance and improve patient o

225 The transcriptional profile of PS-341-treated cells involved down-regulation of growth/

226 e complete tumor regression, was observed in PS-341-treated mice.

227 PS-341 treatment by itself does not affect the levels of

228 , we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on mole

229 TUNEL staining indicated that PS-341 treatment sensitizes Tax tumors to DNA fragmentat

230 We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH(2)

231 -5p, are upregulated by proteasome inhibitor PS-341 treatment, in HepG2 and MDA-MB-453 cells.

232 of SEK-1, JNK, and c-Jun are not induced by PS-341 treatment, suggesting that PS-341 does not trigge

233 t shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers P

234 y and clinical responses achieved in MM with PS-341 treatment.

235 DNA fragmentation factor 45 was triggered by PS-341 treatment.

236 ned antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine.

237 CDDO-Im and bortezomib/proteasome inhibitor PS-341 trigger synergistic apoptosis in MM cells associa

238 t growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as

239 some inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multi

240 n our murine model of adult T-cell leukemia, PS-341 used alone did not yield prolongation of the surv

241 toxicity, and in vivo mechanism of action of PS-341 using a human plasmacytoma xenograft mouse model.

242 , Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which

243 Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of

244 vity of the proteasome inhibitor bortezomib (PS-341, Velcade) observed in clinical trials of patients

245 Bortezomib (PS-341, Velcade), a potent TRAIL-sensitizing agent, incr

246 ines by the proteasome inhibitor bortezomib (PS-341, Velcade).

247 The proteasome inhibitor bortezomib (PS-341, Velcade; Millennium Pharmaceuticals, Cambridge,

248 nhibition of the proteasome with bortezomib (PS-341/Velcade) also rescued CFTR, but with less efficie

249 oteasome inhibitor bortezomib (also known as PS-341/Velcade) is a dipeptidyl boronic acid that has re

250 proved drug humanized anti-Tac, therapy with PS-341 was associated with a complete remission in a pro

251 nhibitor, the apoptosis-inducing activity of PS-341 was dramatically enhanced.

252 say to follow the biological activity of the PS-341 was established and used to determine temporal dr

253 The PD of PS-341 was evaluated by measurement of whole blood 20S p

254 As such, PS-341 was shown to penetrate PC-3 tumors and inhibit in

255 PS-341 was well tolerated at 1.04 mg/m(2) on this dose-i

256 PS-341 was well tolerated up to 0.5 mg/kg, but some mice

257 antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells.

258 ors of the proteasome, exemplified herein by PS-341, were developed.

259 eating the cells with a proteasome inhibitor PS-341 which blocks intracellular degradation of IkappaB

260 The peptide boronic acid compound PS-341, which was designed to inhibit proteasome chymotr

261 ies of proteasome inhibitors, exemplified by PS-341, which we describe here.

262 Preclinical studies have shown that PS-341 will also potentiate the cytotoxic effects of rad

263 bservations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP.

264 ed in a rapid and widespread distribution of PS-341, with highest levels identified in the liver and

265 a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing.

266 ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol.