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

Second mitochondria-derived activator of caspases (Smac) promotes apoptosis via activation of caspases. Here we show that a low-molecular-weight Smac mimetic LBW242 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib therapies. Examination of purified patient MM cells demonstrated similar results, without significant cytotoxicity against normal lymphocytes and bone marrow stromal cells (BMSCs). Importantly, LBW242 abrogates paracrine MM cell growth triggered by their adherence to BMSCs and overcomes MM cell growth and drug-resistance conferred by interleukin-6 or insulinlike growth factor-1. Overexpression of Bcl-2 similarly does not affect LBW242-induced cytotoxicity. Mechanistic studies show that LBW242-induced apoptosis in MM cells is associated with activation of caspase-8, caspase-9, and caspase-3, followed by PARP cleavage. In human MM xenograft mouse models, LBW242 is well tolerated, inhibits tumor growth, and prolongs survival. Importantly, combining LBW242 with novel agents, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the proteasome inhibitors bortezomib and NPI-0052, as well as with the conventional anti-MM agent melphalan, induces additive/synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM.
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PMID:Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). 1703 24

Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO(*) in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH(2)-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.
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PMID:JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. 1738 1

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

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.
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PMID:Homoharringtonine induces apoptosis and growth arrest in human myeloma cells. 1761 69

Bortezomib is a proteasome inhibitor for the treatment of relapsed/refractory multiple myeloma (MM). Mechanisms of resistance to Bortezomib are undefined. Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic protein, which protects tumor cells against spontaneous and chemotherapy-induced apoptosis. In MM, specific downregulation of Mcl-1 induces apoptosis. Here, we examined the role of Mcl-1 in Bortezomib- and doxorubicin-induced apoptosis. We demonstrate that Bortezomib, but not doxorubicin, triggers caspase-dependent generation of a 28 kDa Mcl-1-fragment, in several MM cell lines, including MM.1S cells. Conversely, transient transfection of MM.1S cells with a previously reported 28 kDa Mcl-1(128-350) fragment, but not with the Mcl-1(1-127) fragment, induces apoptosis. Therefore, both downregulation of full-length antiapoptotic Mcl-1, as well as Bortezomib-induced generation of Mcl-1(128-350) cleaved protein, contribute to MM cell apoptosis. To verify further these findings, we next compared effects triggered by Bortezomib, doxorubicin and melphalan in Mcl-1(wt/wt) and Mcl-1(Delta/null) murine embryonic fibroblasts (MEFs). Our results show that Bortezomib, but not doxorubicin or melphalan, triggers Mcl-1 cleavage in Mcl-1(wt/wt), but not Mcl-1(Delta/null) MEFs and induces sub-G(1) phase cells; caspase-3 and -9, and PARP cleavage as well as morphological signs of apoptosis. Taken together, these results support an important role of Mcl-1 and a Mcl-1 fragment in Bortezomib-induced cell death in general, and in MM in particular. To prevent relapse of MM in patients treated with Bortezomib, we therefore recommend the combination of Bortezomib with agents that induce MM cell death independent of Mcl-1.
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PMID:A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. 1765 83

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.
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PMID:Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. 1800 97

To ascertain the exact anti-myeloma mechanism of thalidomide in vivo, we performed structural development studies of thalidomide, and obtained various analogues with specific molecular properties. Among these derivatives, we found that a new thalidomide analogue, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33) had the most potent anti-myeloma effect and tubulin-polymerization-inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cell lines (RPMI8226, U266, and IM9) in a dose-dependent manner with IC50 of 1-10 microM. In contrast, thalidomide itself did not inhibit cellular growth of RPMI8226 cells. Cultivation with 10 microM 5HPP-33 induced G2/M phase cell cycle arrest, followed by apoptosis of myeloma cells. Treatment with 5HPP-33 induced caspase-3 activity and PARP cleavage. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 showed potent tubulin-polymerization-inhibiting activity with IC50 of 8.1 microM, comparable to that of the known tubulin-polymerization inhibitor, rhizoxin. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Notably, the structural requirement for its activity was critical, as other analogues and derivatives of 5HPP-33 showed only slight tubulin-polymerization-inhibiting activity. Our data suggest that 5HPP-33 is a promising candidates for a therapeutic agent of multiple myeloma. In addition, these results suggest that the tubulin-polymerization inhibiting activity of thalidomide might be a possible mechanism for inducing the apoptosis of myeloma cells by thalidomide.
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PMID:Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: possible anti-myeloma mechanism of thalidomide. 1820 82

Bortezomib (VELCADE), formerly known as PS-341, is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo anti-tumor activity. Bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma. In this report, we examined the sensitivity of cell lines derived from Ewing's sarcoma-family of tumors (ESFT) to Bortezomib. Five ESFT-derived cell lines, TC-71, TC-32, SK-N-MC, A4573 and GRIMES, were highly sensitive to Bortezomib (IC(50) = 20 to 50 nM), and underwent cell cycle arrest and apoptosis following drug treatment. Bortezomib-induced apoptosis was associated with activation of caspase 3, cleavage of PARP and induction of p27 and p21 expression. Moreover, Bortezomib exhibited synergistic activity against the TC-71 and TC-32 cell lines when combined with TRAIL. Our results suggest that Bortezomib might be a useful agent for treatment of ESFT, when used alone or in combination with TRAIL.
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PMID:Proteasome inhibitor Bortezomib induces cell cycle arrest and apoptosis in cell lines derived from Ewing's sarcoma family of tumors and synergizes with TRAIL. 1822 18

This study investigated the biological significance of the inhibition of fatty acid synthase (FAS) in multiple myeloma (MM) using the small molecule inhibitor Cerulenin. Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of caspase -8, -9, -3 and PARP; moreover, the pan-caspase inhibitor Z-VAD-FMK did not inhibit Cerulenin-induced apoptosis and cell death. In addition, treatment of MM cells with Cerulenin primarily up-regulated apoptosis-inducing factor/endonuclease G, mediators of caspase-independent apoptosis. Importantly, Cerulenin induced endoplasmic reticulum stress response via up-regulation of the Grp78/IRE1alpha/JNK pathway. Although the C-Jun-NH(2)-terminal kinase (JNK) inhibitor SP600215 blocked Cerulenin-induced cytotoxicity, it did not inhibit apoptosis and caspase cleavage. Furthermore, Cerulenin showed synergistic cytotoxic effects with various agents including Bortezomib, Melphalan and Doxorubicin. Our results therefore indicate that inhibition of FAS by Cerulenin primarily triggered caspase-independent apoptosis and JNK-dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti-tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM.
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PMID:Fatty acid synthase is a novel therapeutic target in multiple myeloma. 2071 68

The interaction of multiple myeloma (MM) cells with their microenvironment in the bone marrow (BM) provides a protective environment and resistance to therapeutic agents. We hypothesized that disruption of the interaction of MM cells with their BM milieu would lead to their sensitization to therapeutic agents such as bortezomib, melphalan, doxorubicin, and dexamethasone. We report that the CXCR4 inhibitor AMD3100 induces disruption of the interaction of MM cells with the BM reflected by mobilization of MM cells into the circulation in vivo, with kinetics that differed from that of hematopoietic stem cells. AMD3100 enhanced sensitivity of MM cell to multiple therapeutic agents in vitro by disrupting adhesion of MM cells to bone marrow stromal cells (BMSCs). Moreover, AMD3100 increased mobilization of MM cells to the circulation in vivo, increased the ratio of apoptotic circulating MM cells, and enhanced the tumor reduction induced by bortezomib. Mechanistically, AMD3100 significantly inhibited Akt phosphorylation and enhanced poly(ADP-ribose) polymerase (PARP) cleavage as a result of bortezomib, in the presence of BMSCs in coculture. These experiments provide a proof of concept for the use of agents that disrupt interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy.
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PMID:CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. 1962 18


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