The Experts below are selected from a list of 930 Experts worldwide ranked by ideXlab platform
Hiroshi Yasui - One of the best experts on this subject based on the ideXlab platform.
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NEOPLASIA SDX-101, the R-enantiomer of Etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma
2016Co-Authors: Hiroshi Yasui, Teru Hideshima, Norihiko Shiraishi, Kenji Ishitsuka, Noopur Raje, Makoto Hamasaki, Aldo M Roccaro, Pierfrancesco Tassone, Shaji Kumar, Yu-tzu TaiAbstract:In this study we report that R-Etodolac (SDX-101), at clinically relevant concentra-tions, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)–, doxorubicin (Dox40/RPMI8226)–, and bort-ezomib (DHL4)–resistant cell lines. Immu-noblot analysis demonstrates that R-Etodolac induces apoptosis characterized by caspase-8,-9, and-3 and PARP (poly-ADP [adenosine diphosphate]–ribose polymerase) cleavage and down-regula-tion of cyclin D1 expression. Subcyto-toxic doses of R-Etodolac up-regulate my-eloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexametha-sone (Dex)–induced caspase activation and apoptosis. The combination of R-Etodolac with Dex results in a highly synergistic cytotoxic effect. R-Etodolac also induces apoptosis against primary cells isolated from patients with MM re-fractory to chemotherapy. Although inter-leukin 6 (IL-6) and insulin-like growth factor-1 (IGF-1) abrogate Dex-induced MM cell cytotoxicity, neither IL-6 nor IGF-1 protects against R-Etodolac–induced cy-totoxicity in MM cells. R-Etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSCs), thereby overcoming a mechanism of drug resistance commonly observed with other conventional chemotherapeutic agents. Our data, therefore, indicate that R-Etodolac circumvents drug resistance in MM cells at clinically relevant concen-trations, targets Mcl-1, and can be syner-gistically combined with Dex. (Blood
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of β catenin tcf pathway
Leukemia, 2007Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Kumar SukhdeoAbstract:We have reported previously that R-enantiomer of Etodolac (R-Etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits β-catenin/T-cell factor pathway by inhibiting nuclear translocation of β-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 can target MM cells in the BM milieu.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of wnt β catenin pathway
Blood, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Shweta ChhetriAbstract:Abstract In a previous study we reported that R-enantiomer of Etodolac (R-Etodolac) which is under investigation in Phase II clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in both drug-sensitive and drug-resistant multiple myeloma (MM) cell lines, as well as in patient MM tumor cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against MM cell lines and tumor cells from patients with refractory MM. It also induces cytotoxicity against bortezomib-resistant tumor cells. The molecular mechanisms whereby SDX-308 triggers MM cell cytotoxicity were next delineated. SDX-308 induces apoptosis via caspase-8/-9/-3 activation and poly(ADP-ribose) polymerase PARP cleavage. It strongly inhibits Wnt/β-catenin pathway by blockade of nuclear translocation of β-catenin, followed by significant inhibition of transcription and expression of target proteins. These target proteins include cell cycle regulatory c-myc molecules and anti-apoptotic survivin molecules. Neither interleukin-6 nor insulin-like growth factor-1, which induce MM cell growth and abrogate Dex-induced apoptosis, protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 has more potent cytotoxicity in MM cells than R-Etodolac even in the context with BM microenvironment, providing the preclinical rationale to conduct clinical trials of this agent to improve patient outcome in MM.
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in vivo and in vitro cytotoxicity of r Etodolac with dexamethasone in glucocorticoid resistant multiple myeloma cells
British Journal of Haematology, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Catley P Laurence, Noopur Raje, Pierfrancesco Tassone, Kenji IshitsukaAbstract:SummaryGlucocorticoids have been widely used in the treatment of multiple myeloma(MM) both as single agents and in combination with other drugs. However,primary or acquired glucocorticoid resistance occurs in most cases. It wasrecently reported that R-Etodolac induced in vitro cytotoxicity in MM celllines and in primary MM cells, as well as synergistically enhanceddexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells.This study examined the in vitro and in vivo effects of combinationtreatment with R-Etodolac and Dex on Dex-resistant OPM1 cells. Treatmentwith R-Etodolac and Dex was found to enhance cytotoxicity, inhibit nuclearfactor jB activity via upregulation of IjBa, as well as enhance Dex-inducedcaspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells.R-Etodolac also enhanced Dex cytotoxicity in patient MM cells that wereresistant to glucocorticoids. The in vivo anti-tumour effect of thiscombination on MM cells was evaluated by using severe combinedimmunodeficient mice engrafted with OPM1. Treatment with R-Etodolacor Dex alone did not induce a significant reduction of tumour volume; incontrast, combination treatment with R-Etodolac and Dex inducedsignificant synergistic inhibition of tumour growth. These data indicatethat R-Etodolac overcomes resistance to Dex in glucocorticoid-resistant MMcells, providing the framework for clinical trials of R-Etodolac combined withDex, to improve patient outcome in MM.Keywords: R-Etodolac, multiple myeloma, dexamethasone, drug resistance,in vivo mouse model.
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r Etodolac and a novel indole pyran structural analog sdx 308 induce cytotoxicity and overcome drug resistance in multiple myeloma
Blood, 2005Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Janice Jin, Tanyel Kiziltepe, Norihiko Shiraishi, Kenji Ishitsuka, Catley P Laurence, Noopur RajeAbstract:SDX-101, the less toxic R-isomer of the commercially available non-steroidal inflammatory drug R,S-Etodolac (Lodine®), lacks COX inhibitory activity and is being investigated in Phase II clinical trials in chronic lymphocytic leukemia. Recently, we reported that R-Etodolac, at clinically relevant concentrations, induces potent in vitro cytotoxicity in drug-sensitive and conventional drug-resistant multiple myeloma (MM) cell lines, as well as in primary tumor cells from MM patients. R-Etodolac triggers caspase/poly-ADP-ribose polymerase (PARP) cleavage and downregulates of cyclin D1 expression (Yasui et al. Blood 2005). Importantly, R-Etodolac at sub-cytotoxic doses upregulates Mcl-1 s and synergistically enhances dexamethasone (Dex)-induced caspase-dependent apoptosis in Dex-sensitive MM.1S cells. Combination of R-Etodolac with Dex enhances cytotoxicity in Dex resistant OPM1 MM cells and in Dex-resistant patient MM cells in vitro . We further studied the in vivo anti-tumor effect of combined R-Etodolac and Dex in SCID mice injected subcutaneously with OPM1 human MM cells. While oral treatment of SCID mice with R-Etodolac alone (250 mg/kg/d) or Dex alone (1 mg/kg/d) did not induce any significant reduction of tumor volume compared with control (PBS), the combination of R-Etodolac and Dex inhibited tumor growth synergistically (synergism quotient = 1.6) and significantly ( p = 0.023), suggesting that R-Etodolac may reverse Dex resistance in MM. Finally, we demonstrated that racemic SDX-308, a novel indole-pyran structural analog of Etodolac, has 10-fold more potent cytotoxicity than R-Etodolac in MM cell lines both sensitive and resistant to conventional therapies, as well as in patient’s MM cells. Moreover, SDX-308, like R-Etodolac, can overcome the viability and proliferative enhancing effects of exogeneous IL-6, IGF-1, or bone marrow stroma cells. These combined observations indicate that SDX-308 is a promising more potent second generation analog of R-Etodolac for MM therapy. Our data suggest that R-Etodolac and its novel analog SDX-308 overcome resistance to some conventional therapeutics used for MM, and provide preclinical rationale to conduct clinical trials of R-Etodolac and SDX-308 to treat MM.
Paola Neri - One of the best experts on this subject based on the ideXlab platform.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of β catenin tcf pathway
Leukemia, 2007Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Kumar SukhdeoAbstract:We have reported previously that R-enantiomer of Etodolac (R-Etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits β-catenin/T-cell factor pathway by inhibiting nuclear translocation of β-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 can target MM cells in the BM milieu.
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in vivo and in vitro cytotoxicity of r Etodolac with dexamethasone in glucocorticoid resistant multiple myeloma cells
British Journal of Haematology, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Catley P Laurence, Noopur Raje, Pierfrancesco Tassone, Kenji IshitsukaAbstract:SummaryGlucocorticoids have been widely used in the treatment of multiple myeloma(MM) both as single agents and in combination with other drugs. However,primary or acquired glucocorticoid resistance occurs in most cases. It wasrecently reported that R-Etodolac induced in vitro cytotoxicity in MM celllines and in primary MM cells, as well as synergistically enhanceddexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells.This study examined the in vitro and in vivo effects of combinationtreatment with R-Etodolac and Dex on Dex-resistant OPM1 cells. Treatmentwith R-Etodolac and Dex was found to enhance cytotoxicity, inhibit nuclearfactor jB activity via upregulation of IjBa, as well as enhance Dex-inducedcaspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells.R-Etodolac also enhanced Dex cytotoxicity in patient MM cells that wereresistant to glucocorticoids. The in vivo anti-tumour effect of thiscombination on MM cells was evaluated by using severe combinedimmunodeficient mice engrafted with OPM1. Treatment with R-Etodolacor Dex alone did not induce a significant reduction of tumour volume; incontrast, combination treatment with R-Etodolac and Dex inducedsignificant synergistic inhibition of tumour growth. These data indicatethat R-Etodolac overcomes resistance to Dex in glucocorticoid-resistant MMcells, providing the framework for clinical trials of R-Etodolac combined withDex, to improve patient outcome in MM.Keywords: R-Etodolac, multiple myeloma, dexamethasone, drug resistance,in vivo mouse model.
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r Etodolac and a novel indole pyran structural analog sdx 308 induce cytotoxicity and overcome drug resistance in multiple myeloma
Blood, 2005Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Janice Jin, Tanyel Kiziltepe, Norihiko Shiraishi, Kenji Ishitsuka, Catley P Laurence, Noopur RajeAbstract:SDX-101, the less toxic R-isomer of the commercially available non-steroidal inflammatory drug R,S-Etodolac (Lodine®), lacks COX inhibitory activity and is being investigated in Phase II clinical trials in chronic lymphocytic leukemia. Recently, we reported that R-Etodolac, at clinically relevant concentrations, induces potent in vitro cytotoxicity in drug-sensitive and conventional drug-resistant multiple myeloma (MM) cell lines, as well as in primary tumor cells from MM patients. R-Etodolac triggers caspase/poly-ADP-ribose polymerase (PARP) cleavage and downregulates of cyclin D1 expression (Yasui et al. Blood 2005). Importantly, R-Etodolac at sub-cytotoxic doses upregulates Mcl-1 s and synergistically enhances dexamethasone (Dex)-induced caspase-dependent apoptosis in Dex-sensitive MM.1S cells. Combination of R-Etodolac with Dex enhances cytotoxicity in Dex resistant OPM1 MM cells and in Dex-resistant patient MM cells in vitro . We further studied the in vivo anti-tumor effect of combined R-Etodolac and Dex in SCID mice injected subcutaneously with OPM1 human MM cells. While oral treatment of SCID mice with R-Etodolac alone (250 mg/kg/d) or Dex alone (1 mg/kg/d) did not induce any significant reduction of tumor volume compared with control (PBS), the combination of R-Etodolac and Dex inhibited tumor growth synergistically (synergism quotient = 1.6) and significantly ( p = 0.023), suggesting that R-Etodolac may reverse Dex resistance in MM. Finally, we demonstrated that racemic SDX-308, a novel indole-pyran structural analog of Etodolac, has 10-fold more potent cytotoxicity than R-Etodolac in MM cell lines both sensitive and resistant to conventional therapies, as well as in patient’s MM cells. Moreover, SDX-308, like R-Etodolac, can overcome the viability and proliferative enhancing effects of exogeneous IL-6, IGF-1, or bone marrow stroma cells. These combined observations indicate that SDX-308 is a promising more potent second generation analog of R-Etodolac for MM therapy. Our data suggest that R-Etodolac and its novel analog SDX-308 overcome resistance to some conventional therapeutics used for MM, and provide preclinical rationale to conduct clinical trials of R-Etodolac and SDX-308 to treat MM.
Hiroshi Ikeda - One of the best experts on this subject based on the ideXlab platform.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of β catenin tcf pathway
Leukemia, 2007Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Kumar SukhdeoAbstract:We have reported previously that R-enantiomer of Etodolac (R-Etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits β-catenin/T-cell factor pathway by inhibiting nuclear translocation of β-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 can target MM cells in the BM milieu.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of wnt β catenin pathway
Blood, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Shweta ChhetriAbstract:Abstract In a previous study we reported that R-enantiomer of Etodolac (R-Etodolac) which is under investigation in Phase II clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in both drug-sensitive and drug-resistant multiple myeloma (MM) cell lines, as well as in patient MM tumor cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against MM cell lines and tumor cells from patients with refractory MM. It also induces cytotoxicity against bortezomib-resistant tumor cells. The molecular mechanisms whereby SDX-308 triggers MM cell cytotoxicity were next delineated. SDX-308 induces apoptosis via caspase-8/-9/-3 activation and poly(ADP-ribose) polymerase PARP cleavage. It strongly inhibits Wnt/β-catenin pathway by blockade of nuclear translocation of β-catenin, followed by significant inhibition of transcription and expression of target proteins. These target proteins include cell cycle regulatory c-myc molecules and anti-apoptotic survivin molecules. Neither interleukin-6 nor insulin-like growth factor-1, which induce MM cell growth and abrogate Dex-induced apoptosis, protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 has more potent cytotoxicity in MM cells than R-Etodolac even in the context with BM microenvironment, providing the preclinical rationale to conduct clinical trials of this agent to improve patient outcome in MM.
Teru Hideshima - One of the best experts on this subject based on the ideXlab platform.
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NEOPLASIA SDX-101, the R-enantiomer of Etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma
2016Co-Authors: Hiroshi Yasui, Teru Hideshima, Norihiko Shiraishi, Kenji Ishitsuka, Noopur Raje, Makoto Hamasaki, Aldo M Roccaro, Pierfrancesco Tassone, Shaji Kumar, Yu-tzu TaiAbstract:In this study we report that R-Etodolac (SDX-101), at clinically relevant concentra-tions, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)–, doxorubicin (Dox40/RPMI8226)–, and bort-ezomib (DHL4)–resistant cell lines. Immu-noblot analysis demonstrates that R-Etodolac induces apoptosis characterized by caspase-8,-9, and-3 and PARP (poly-ADP [adenosine diphosphate]–ribose polymerase) cleavage and down-regula-tion of cyclin D1 expression. Subcyto-toxic doses of R-Etodolac up-regulate my-eloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexametha-sone (Dex)–induced caspase activation and apoptosis. The combination of R-Etodolac with Dex results in a highly synergistic cytotoxic effect. R-Etodolac also induces apoptosis against primary cells isolated from patients with MM re-fractory to chemotherapy. Although inter-leukin 6 (IL-6) and insulin-like growth factor-1 (IGF-1) abrogate Dex-induced MM cell cytotoxicity, neither IL-6 nor IGF-1 protects against R-Etodolac–induced cy-totoxicity in MM cells. R-Etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSCs), thereby overcoming a mechanism of drug resistance commonly observed with other conventional chemotherapeutic agents. Our data, therefore, indicate that R-Etodolac circumvents drug resistance in MM cells at clinically relevant concen-trations, targets Mcl-1, and can be syner-gistically combined with Dex. (Blood
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of β catenin tcf pathway
Leukemia, 2007Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Kumar SukhdeoAbstract:We have reported previously that R-enantiomer of Etodolac (R-Etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits β-catenin/T-cell factor pathway by inhibiting nuclear translocation of β-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 can target MM cells in the BM milieu.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of wnt β catenin pathway
Blood, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Shweta ChhetriAbstract:Abstract In a previous study we reported that R-enantiomer of Etodolac (R-Etodolac) which is under investigation in Phase II clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in both drug-sensitive and drug-resistant multiple myeloma (MM) cell lines, as well as in patient MM tumor cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against MM cell lines and tumor cells from patients with refractory MM. It also induces cytotoxicity against bortezomib-resistant tumor cells. The molecular mechanisms whereby SDX-308 triggers MM cell cytotoxicity were next delineated. SDX-308 induces apoptosis via caspase-8/-9/-3 activation and poly(ADP-ribose) polymerase PARP cleavage. It strongly inhibits Wnt/β-catenin pathway by blockade of nuclear translocation of β-catenin, followed by significant inhibition of transcription and expression of target proteins. These target proteins include cell cycle regulatory c-myc molecules and anti-apoptotic survivin molecules. Neither interleukin-6 nor insulin-like growth factor-1, which induce MM cell growth and abrogate Dex-induced apoptosis, protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 has more potent cytotoxicity in MM cells than R-Etodolac even in the context with BM microenvironment, providing the preclinical rationale to conduct clinical trials of this agent to improve patient outcome in MM.
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in vivo and in vitro cytotoxicity of r Etodolac with dexamethasone in glucocorticoid resistant multiple myeloma cells
British Journal of Haematology, 2006Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Catley P Laurence, Noopur Raje, Pierfrancesco Tassone, Kenji IshitsukaAbstract:SummaryGlucocorticoids have been widely used in the treatment of multiple myeloma(MM) both as single agents and in combination with other drugs. However,primary or acquired glucocorticoid resistance occurs in most cases. It wasrecently reported that R-Etodolac induced in vitro cytotoxicity in MM celllines and in primary MM cells, as well as synergistically enhanceddexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells.This study examined the in vitro and in vivo effects of combinationtreatment with R-Etodolac and Dex on Dex-resistant OPM1 cells. Treatmentwith R-Etodolac and Dex was found to enhance cytotoxicity, inhibit nuclearfactor jB activity via upregulation of IjBa, as well as enhance Dex-inducedcaspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells.R-Etodolac also enhanced Dex cytotoxicity in patient MM cells that wereresistant to glucocorticoids. The in vivo anti-tumour effect of thiscombination on MM cells was evaluated by using severe combinedimmunodeficient mice engrafted with OPM1. Treatment with R-Etodolacor Dex alone did not induce a significant reduction of tumour volume; incontrast, combination treatment with R-Etodolac and Dex inducedsignificant synergistic inhibition of tumour growth. These data indicatethat R-Etodolac overcomes resistance to Dex in glucocorticoid-resistant MMcells, providing the framework for clinical trials of R-Etodolac combined withDex, to improve patient outcome in MM.Keywords: R-Etodolac, multiple myeloma, dexamethasone, drug resistance,in vivo mouse model.
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r Etodolac and a novel indole pyran structural analog sdx 308 induce cytotoxicity and overcome drug resistance in multiple myeloma
Blood, 2005Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Janice Jin, Tanyel Kiziltepe, Norihiko Shiraishi, Kenji Ishitsuka, Catley P Laurence, Noopur RajeAbstract:SDX-101, the less toxic R-isomer of the commercially available non-steroidal inflammatory drug R,S-Etodolac (Lodine®), lacks COX inhibitory activity and is being investigated in Phase II clinical trials in chronic lymphocytic leukemia. Recently, we reported that R-Etodolac, at clinically relevant concentrations, induces potent in vitro cytotoxicity in drug-sensitive and conventional drug-resistant multiple myeloma (MM) cell lines, as well as in primary tumor cells from MM patients. R-Etodolac triggers caspase/poly-ADP-ribose polymerase (PARP) cleavage and downregulates of cyclin D1 expression (Yasui et al. Blood 2005). Importantly, R-Etodolac at sub-cytotoxic doses upregulates Mcl-1 s and synergistically enhances dexamethasone (Dex)-induced caspase-dependent apoptosis in Dex-sensitive MM.1S cells. Combination of R-Etodolac with Dex enhances cytotoxicity in Dex resistant OPM1 MM cells and in Dex-resistant patient MM cells in vitro . We further studied the in vivo anti-tumor effect of combined R-Etodolac and Dex in SCID mice injected subcutaneously with OPM1 human MM cells. While oral treatment of SCID mice with R-Etodolac alone (250 mg/kg/d) or Dex alone (1 mg/kg/d) did not induce any significant reduction of tumor volume compared with control (PBS), the combination of R-Etodolac and Dex inhibited tumor growth synergistically (synergism quotient = 1.6) and significantly ( p = 0.023), suggesting that R-Etodolac may reverse Dex resistance in MM. Finally, we demonstrated that racemic SDX-308, a novel indole-pyran structural analog of Etodolac, has 10-fold more potent cytotoxicity than R-Etodolac in MM cell lines both sensitive and resistant to conventional therapies, as well as in patient’s MM cells. Moreover, SDX-308, like R-Etodolac, can overcome the viability and proliferative enhancing effects of exogeneous IL-6, IGF-1, or bone marrow stroma cells. These combined observations indicate that SDX-308 is a promising more potent second generation analog of R-Etodolac for MM therapy. Our data suggest that R-Etodolac and its novel analog SDX-308 overcome resistance to some conventional therapeutics used for MM, and provide preclinical rationale to conduct clinical trials of R-Etodolac and SDX-308 to treat MM.
Kumar Sukhdeo - One of the best experts on this subject based on the ideXlab platform.
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novel Etodolac analog sdx 308 cep 18082 induces cytotoxicity in multiple myeloma cells associated with inhibition of β catenin tcf pathway
Leukemia, 2007Co-Authors: Hiroshi Yasui, Teru Hideshima, Paola Neri, Tanyel Kiziltepe, Hiroshi Ikeda, Enrique M Ocio, Sonia Vallet, Yutaka Okawa, Kumar SukhdeoAbstract:We have reported previously that R-enantiomer of Etodolac (R-Etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of Etodolac, has more potent cytotoxicity than R-Etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits β-catenin/T-cell factor pathway by inhibiting nuclear translocation of β-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel Etodolac analog SDX-308 can target MM cells in the BM milieu.