Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.
 ...
PMID:A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells. 1296 89

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
 ...
PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6

These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNF alpha related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNF alpha related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNF alpha /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-kappa B and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-kappa B, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
 ...
PMID:RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells. 1531 84

Triptolide has been reported to be effective in the treatment of auto-immune diseases. This study investigates the cytotoxic function of triptolide on multiple myeloma (MM) cells. We found that triptolide inhibited the proliferation of both RPMI8226 and U266 cells in a dose-dependent manner (10-80 ng/mL). Triptolide induced apoptosis in MM cells through activation of the cystein protease caspase 8, 9 and 3, and subsequent cleavage of the DNA repair enzyme poly (ADP-ribose) polymerase. Apoptosis was confirmed with cell-cycle analysis and annexin V staining. Moreover, triptolide down-regulated nuclear factor (NF)-kappaB activity in MM cell lines. In addition, triptolide also induced chemosensitivity to doxorubicin and suppressed cell proliferation of fresh MM cells. Therefore, triptolide appears to be a potent inducer of apoptosis in myeloma cells, and might have some benefit in the treatment of myeloma patients.
 ...
PMID:Triptolide inhibits transcription factor NF-kappaB and induces apoptosis of multiple myeloma cells. 1554 81

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 beta-catenin/T-cell factor pathway by inhibiting nuclear translocation of beta-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.
 ...
PMID:Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway. 1726 21

Homoharringtonine (HHT) is a plant alkaloid with antileukemic activity which is currently being used for treatment of acute and chronic leukemias. The present studies have evaluated the effect of HHT on proliferation and apoptosis in human myeloma cells. Myeloma cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic cells and cell cycle were evaluated by flow cytometry. Level of caspase-8, caspase-9, caspase-3, and DNA repair enzyme poly (ADP-ribose) polymerase (PARP), were investigated using Western blot analysis. We found that HHT significantly inhibited the proliferation of human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM in a dose-dependent manner. HHT also induced apoptosis in myeloma cells as evidenced by flow cytometric detection of annexin V binding assay. This apoptotic process was associated with the activation of caspase-8, caspase-9, caspase-3 and PARP. The results also demonstrate that HHT potentiates dexamethasone-induced killing of MM cells. These findings indicate that HHT may be effective in the treatment of MM.
 ...
PMID:Homoharringtonine induces apoptosis and growth arrest in human myeloma cells. 1761 69

Akt mediates growth and drug resistance in multiple myeloma (MM) cells in the bone marrow (BM) microenvironment. We have shown that a novel Akt inhibitor Perifosine induces significant cytotoxicity in MM cells in the BM milieu. This study further delineated molecular mechanisms whereby Perifosine triggered cytotoxicity in MM cells. Neither the intensity of Jun NH(2)-terminal kinase phosphorylation nor caspase/poly (ADP-ribose) polymerase cleavage correlated with Perifosine-induced cytotoxicity in MM.1S, INA6, OPM1 and OPM2 MM cells. However, survivin, which regulates caspase-3 activity, was markedly downregulated by Perifosine treatment, without changes in other anti-apoptotic proteins. Downregulation of survivin by siRNA significantly inhibited OPM1 MM cell growth, confirming that survivin mediates MM cell survival. Perifosine significantly downregulated both function and protein expression of beta-catenin. Co-culture with BM stromal cells (BMSCs) upregulated both beta-catenin and survivin expression in MM cells, which was blocked by Perifosine. Importantly, Perifosine treatment also downregulated survivin expression in human MM cells grown in vivo in a severe combined immunodeficient mouse xenograft model. Finally, Perifosine inhibited bortezomib-induced upregulation of survivin, associated with enhanced cytotoxicity of combined bortezomib and Perifosine treatment. These preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to improve patient outcome in MM.
 ...
PMID:Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. 1776 Aug 10

Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase-8, -9, -3, and poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.
 ...
PMID:SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. 1894 77

Nitrogen-containing bisphosphonates (N-BPs) are effective antiosteolytic agents in patients with multiple myeloma. Preclinical studies have also demonstrated that these agents have direct antitumor effects in vitro and can reduce tumor burden in a variety of animal models, although it is not clear whether such effects are caused by direct actions on tumor cells or by inhibition of bone resorption. N-BPs prevent bone destruction in myeloma by inhibiting the enzyme farnesyl pyrophosphate synthase in osteoclasts, thereby preventing the prenylation of small GTPase signaling proteins. In this study, utilizing a plasmacytoma xenograft model without complicating skeletal lesions, treatment with zoledronic acid (ZOL) led to significant prolongation of survival in severe combined immunodeficiency mice inoculated with human INA-6 plasma cells. Following treatment with a clinically relevant dose of ZOL, histological analysis of INA-6 tumors from the peritoneal cavity revealed extensive areas of apoptosis associated with poly (ADP-ribose) polymerase cleavage. Furthermore, Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by nonskeletal tumors and inhibition of farnesyl pyrophosphate synthase. These studies provide, for the first time, clear evidence that N-BPs have direct antitumor effects in plasma cell tumors in vivo and this is executed by a molecular mechanism similar to that observed in osteoclasts.
 ...
PMID:The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. 1962 90

The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is currently undergoing clinical trials as an antitumor drug. We show here that treatment of human multiple myeloma (MM) cells with 17DMAG induces mTOR inhibition and microtubule-associated protein light chain 3 (LC3) conversion (LC3-I to LC3-II), an indicator of autophagy. Interestingly, 17DMAG synergistically induces apoptosis through a mitochondria-operated pathway in the presence of the autophagy inhibitor 3-methyladenine (3-MA). Inhibition of autophagy by 3-MA facilitated caspase activation, cytochrome c release from mitochondria and poly (ADP-ribose) polymerase (PARP) cleavage in myeloma cells treated with 17DMAG. The potential use of Hsp90 and autophagy inhibitors combinations as a therapeutic tool in MM is further discussed in our work.
 ...
PMID:Autophagy inhibition sensitizes multiple myeloma cells to 17-dimethylaminoethylamino-17-demethoxygeldanamycin-induced apoptosis. 2066 92


1 2 3 Next >>