9 results on '"Hideshima, Teru"'
Search Results
2. BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma.
- Author
-
Dutta, Debasmita, Liu, Jiye, Wen, Kenneth, Kurata, Keiji, Fulciniti, Mariateresa, Gulla, Annamaria, Hideshima, Teru, and Anderson, Kenneth C.
- Subjects
MULTIPLE myeloma ,TREATMENT effectiveness ,BORTEZOMIB ,CELL death ,CYTOTOXINS - Abstract
Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Blockade of the MEK/ERK signaling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo
- Author
-
Kim, Kihyun, Kong, Sun-Young, Fulciniti, Mariateresa, Li, Xianfeng, Song, Weihua, Nahar, Sabikun, Burger, Peter, Rumizen, Mathew J, Podar, Klaus, Chauhan, Dharminder, Hideshima, Teru, Munshi, Nikhil C., Richardson, Paul, Clark, Ann, Ogden, Janet, Goutopoulos, Andreas, Rastelli, Luca, Anderson, Kenneth C., and Tai, Yu-Tzu
- Subjects
Niacinamide ,Cell Death ,Dose-Response Relationship, Drug ,MAP Kinase Signaling System ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,Antineoplastic Agents ,Apoptosis ,Mice, SCID ,Xenograft Model Antitumor Assays ,Article ,Mice ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Animals ,Humans ,Multiple Myeloma ,Protein Kinase Inhibitors - Abstract
This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Significant tumour growth reduction in AS703026- vs. vehicle-treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome.
- Published
- 2010
4. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers.
- Author
-
Cottini, Francesca, Hideshima, Teru, Xu, Chunxiao, Sattler, Martin, Dori, Martina, Agnelli, Luca, ten Hacken, Elisa, Bertilaccio, Maria Teresa, Antonini, Elena, Neri, Antonino, Ponzoni, Maurilio, Marcatti, Magda, Richardson, Paul G, Carrasco, Ruben, Kimmelman, Alec C, Wong, Kwok-Kin, Caligaris-Cappio, Federico, Blandino, Giovanni, Kuehl, W Michael, and Anderson, Kenneth C
- Subjects
- *
ONCOGENES , *DNA damage , *APOPTOSIS , *CELL death , *CANCER cells - Abstract
Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
5. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway.
- Author
-
Ishitsuka, Kenji, Hideshima, Teru, Hamasaki, Makoto, Raje, Noopur, Kumar, Shaji, Podar, Klaus, Le Gouill, Steven, Shiraishi, Norihiko, Yasui, Hiroshi, Roccaro, Aldo M., Yu-Zu Tai, Chauhan, Dharminder, Fram, Robert, Tamura, Kazuo, Jain, Jugnu, and Anderson, Kenneth C.
- Subjects
- *
APOPTOSIS , *CELL death , *PLASMACYTOMA , *ORGANELLES , *PROINSULIN , *CYTOKINES - Abstract
Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP. VX-944 (Vertex Pharmaceuticals, Cambridge, MA, USA) is a small-molecule, selective, noncompetitive inhibitor directed against human IMPDH. In this report, we show that VX-944 inhibits in vitro growth of human multiple myeloma (MM) cell lines via induction of apoptosis. Interleukin-6, insulin-like growth factor-1, or co-culture with bone marrow stromal cells (BMSCs) do not protect against VX-944-induced MM cell growth inhibition. VX-944 induced apoptosis in MM cell lines with only modest activation of caspases 3, 8, and 9. Furthermore, the pan-caspase inhibitor z-VAD-fmk did not inhibit VX-944-induced apoptosis and cell death. During VX-944-induced apoptosis, expressions of Bax and Bak were enhanced, and both apoptosis-inducing factor (AIF) and endonuclease G (Endo G) were released from the mitochondria to cytosol, suggesting that VX-944 triggers apoptosis in MM cells primarily via a caspase-independent, Bax/AIF/Endo G pathway. Importantly, VX-944 augments the cytotoxicity of doxorubicin and melphalan even in the presence of BMSCs. Taken together, our data demonstrate a primarily non-caspase-dependent apoptotic pathway triggered by VX-944, thereby providing a rationale to enhance MM cell cytotoxicity by combining this agent with conventional agents which trigger caspase activation.Oncogene (2005) 24, 5888–5896. doi:10.1038/sj.onc.1208739; published online 6 June 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
6. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma.
- Author
-
Hideshima, Teru, Bradner, James E., Jason Wong, Chauhan, Dharminder, Richardson, Paul, Schreiber, Stuart L, and Anderson, Kenneth C.
- Subjects
- *
PROTEOLYTIC enzymes , *HYDROLASES , *IMMUNE system , *APOPTOSIS , *CELL death , *MICROTUBULES - Abstract
We have shown that the proteasome inhibitor bortezomib (formerly known as P5-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of u-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC50 of 5-20 pM, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2-terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with boil-ezomib mediates significant anti-MM activity, providing the frame- work for clinical evaluation of combined therapy to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
7. Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-ßinhibitors.
- Author
-
Hideshima, Teru, Chauhan, Dharminder, Ishitsuka, Kenji, Yasui, Hiroshi, Raje, Noopur, Kumar, Shaji, Podar, Klaus, Mitsiades, Constantine, Hideshima, Hiromasa, Bonham, Lynn, Munshi, Nikhil C, Richardson, Paul G, Singer, Jack W, and Anderson, Kenneth C
- Subjects
- *
APOPTOSIS , *CELL death , *MONOCLONAL gammopathies , *ANTHRACYCLINES , *LYSOPHOSPHOLIPIDS , *ACYLTRANSFERASES - Abstract
PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65%of patients with relapsed refractory disease in a phase II study do not respond to PS-341. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-ßinhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (i.e., dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we therefore determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor 45 was triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. We here show that phosphorylation of SEK-1, JNK, and c-Jun are not induced by PS-341 treatment, suggesting that PS-341 does not trigger a stress response in DHL-4 cells. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggered swelling and lysis of DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-ßinhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.Oncogene (2005) 24, 3121-3129. doi:10.1038/sj.onc.1208522 Published online 21 February 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
8. Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341.
- Author
-
Chauhan, Dharminder, Li, Guilan, Hideshima, Teru, Podar, Klaus, Shringarpure, Reshma, Mitsiades, Constantine, Munshi, Nikhil, Yew, P. Renee, and Anderson, Kenneth C.
- Subjects
ENZYMES ,UBIQUITIN ,MULTIPLE myeloma ,APOPTOSIS ,INTERLEUKIN-6 ,CELL death - Abstract
The ubiquitin-conjugating enzyme CDC34 (UBC3) is linked to cell cycle progression in diverse cell types; however, its role in multiple myeloma (MM) pathogenesis is unclear. Here, we show that CDC34 is highly expressed in patient MM cells and MM cell lines versus normal cells. Blocking CDC34 using a dominant-negative strategy enhances the anti-MM activity of Bortezomib/ Proteasome inhibitor PS-341, dexamethasone (Dex) and 2-Methoxyestradiol (2ME2). The expression of wild-type CDC34 reduces Dex-induced cytotoxicity in MM cells. Moreover, inhibition of CDC34 enzymatic activity abrogates interleukin-6-induced protection against Dex- induced apoptosis. Together, these findings provide evidence that (1) CDC34 expression is associated with growth and survival of MM cells and (2) blocking CDC34 activity not only enhances anti-MM activity of Bortezomib and 2ME2 but also overcomes IL-6-triggered Dex- resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
9. Intracellular NAD+ depletion enhances bortezomib-induced anti-myeloma activity.
- Author
-
Cagnetta, Antonia, Cea, Michele, Calimeri, Teresa, Acharya, Chirag, Fulciniti, Mariateresa, Yu-Tzu Tai, Hideshima, Teru, Chauhan, Dharminder, Zhong, Mike Y., Patrone, Franco, Nencioni, Alessio, Gobbi, Marco, Richardson, Paul, Munshi, Nikhil, and Anderson, Kenneth C.
- Subjects
- *
NICOTINAMIDE , *MYELOMA proteins , *TUMOR proteins , *MULTIPLE myeloma , *CELL death , *XENOGRAFTS , *APOPTOSIS - Abstract
We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD+ content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD+ depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib resistance. This effect is associated with (1) activation of caspase-8, caspase-9, caspase-3, poly (ADP-ribose) polymerase, and downregulation of Mcl-1; (2) enhanced intracellular NAD+ depletion; (3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; (4) inhibition of nuclear factor κB signaling; and (5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, low-dose combination FK866 and Bortezomib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD+ level represents a major determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof of concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.