Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many of the anticancer drugs in current use are toxic and thus limited in their efficacy. It therefore becomes essential to develop novel chemotherapeutic agents with lower levels of toxicity. The beta-lactam antibiotics have been used for many years to treat bacterial infections with limited or no toxicity. Until now, it has never been shown that beta-lactams could kill tumor cells. Here, for the first time, we have discovered and characterized the apoptosis-inducing properties of a family of novel beta-lactam antibiotics against human leukemia, breast, prostate, and head-and-neck cancer cells. We found that one particular lead compound (lactam 1) with an N-methylthio group was able to induce DNA damage and inhibit DNA replication in Jurkat T cells within a 2-h treatment. This was followed by p38 mitogen-activated protein kinase activation, S phase arrest, and apoptotic cell death. p38 was found to be a central player in beta-lactam-induced apoptosis and resided downstream of DNA damage but upstream of caspase activation. Accompanying caspase-8 activation was cleavage of the pro-apoptotic Bcl-2 family protein Bid, and release of the mitochondrial cytochrome c. This was also associated with activation of caspase-9 and -3. Analogs of lactam 1 in which the N-methylthio group was replaced with other organothio chains exhibited progressive decreased potencies to induce DNA damage, p38 kinase activation, S phase arrest, and apoptosis, demonstrating requirement of the N-methylthio group. Because of the ease of synthesis and structural manipulation, we believe these beta-lactams may have the potential to be developed into anticancer agents.
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PMID:A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage. 1202 96

Taxol is used in chemotherapy regimens against breast and ovarian cancer. Treatment of tumor model cell lines with taxol induces apoptosis, but exact mechanism is not sufficiently understood. Our results demonstrate that in response to taxol, various cell types differentially utilize distinct apoptotic pathways. Using MCF7 breast carcinoma cells transfected with caspase-3 gene, we showed that taxol-induced apoptosis occurred in the absence of caspase-3 and caspase-9 activation. Similar results were obtained with ovarian SKOV3 carcinoma cells, expressing high level of endogenous caspase-3. In contrast, staurosporine-induced apoptosis in these cells was accompanied by proteolytic cleavage of pro-caspase-3 and induction of caspase-3 enzymatic activity. The effect of taxol appears to be cell type-specific, since taxol-induced apoptosis in leukemia U937 cells involved caspase-3 activation step. We conclude that a unique caspase-3 and caspase-9 independent pathway is elicited by taxol to induce apoptosis in human ovarian and breast cancinoma cells.
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PMID:Taxol-induced apoptosis in human SKOV3 ovarian and MCF7 breast carcinoma cells is caspase-3 and caspase-9 independent. 1203 72

Satratoxins have been recognized as potential immunomodulatory agents in outbreaks of building-related illness. Here we report that satratoxin G-treated human leukemia HL-60 cells underwent apoptosis through the action of caspase-3 which was activated by both caspase-8 and caspase-9. Western blot analysis of caspase-3 in the satratoxin G-treated cells apparently indicated the appearance of a catalytically active fragment of 17 kDa. Increased caspase-3 activity was also detected by using a fluorogenic substrate, DEVD-AMC. Next, exposure to satratoxin G led to cleavage of PARP from its native 116 kDa form to a 85 kDa product. Moreover, DFF-45/ICAD were cleaved into a 12.5 kDa fragment via satratoxin G treatment. Enzymic assay on IETD-AMC revealed that caspase-8 is strongly activated by exposure to satratoxin G while T-2 toxin (T-2) could not activate caspase-8 at an early stage of apoptosis. Furthermore, satratoxin G caused a release of cytochrome c from mitochondria into the cytosol and increased the activity of caspase-9 against LEHD-AMC. These findings indicate that satratoxin G-induced apoptosis involves activation of caspase-3 and DFF-40/CAD through both activation of caspase-8 and cytosolic accumulation of cytochrome c along with activation of caspase-9.
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PMID:Molecular mechanism of satratoxin-induced apoptosis in HL-60 cells: activation of caspase-8 and caspase-9 is involved in activation of caspase-3. 1216 Dec 80

Huntingtin-interacting protein 1 (HIP1) is a cofactor in clathrin-mediated vesicle trafficking. It was first implicated in cancer biology as part of a chromosomal translocation in leukemia. Here we report that HIP1 is expressed in prostate and colon tumor cells, but not in corresponding benign epithelia. The relationship between HIP1 expression in primary prostate cancer and clinical outcomes was evaluated with tissue microarrays. HIP1 expression was significantly associated with prostate cancer progression and metastasis. Conversely, primary prostate cancers lacking HIP1 expression consistently showed no progression after radical prostatectomy. In addition, the expression of HIP1 was elevated in prostate tumors from the transgenic mouse model of prostate cancer (TRAMP). At the molecular level, expression of a dominant negative mutant of HIP1 led to caspase-9-dependent apoptosis, suggesting that HIP1 is a cellular survival factor. Thus, HIP1 may play a role in tumorigenesis by allowing the survival of precancerous or cancerous cells. HIP1 might accomplish this via regulation of clathrin-mediated trafficking, a fundamental cellular pathway that has not previously been associated with tumorigenesis. HIP1 represents a putative prognostic factor for prostate cancer and a potential therapy target in prostate as well as colon cancers.
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PMID:Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. 1216 54

Imperatorin, a biologically active furanocoumarin from the roots of Angelica dahurica (Umbelliferae), was found to induce apoptosis in human promyelocytic leukaemia, HL-60 cells. DNA fragmentation assay, morphology-based evaluation, and flow cytometric analysis demonstrated that imperatorin at micromolar concentrations was able to trigger apoptosis of HL-60 cells. Neither necrosis nor differentiation was observed at cytotoxic micromolar concentrations of imperatorin. Further studies showed that the cytochrome c/caspase-9 pathway was responsible for imperatorin-induced apoptosis; i.e., mitochondrial membrane was depolarized, Bcl-2 was down-regulated, cytochrome c was released from mitochondria, caspase-9 and caspase-3 were activated, and poly(ADP-ribose) polymerase was cleaved. Furthermore, imperatorin-induced apoptosis was significantly blocked by Z-VAD-FMK (a broad spectrum caspase inhibitor), Z-LEHD-FMK (a caspase-9 inhibitor) and Ac-DMQD-CHO (a caspase-3 inhibitor), but not by Z-IEDT-FMK (a caspase-8 inhibitor).
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PMID:Imperatorin, a furanocoumarin from Angelica dahurica (Umbelliferae), induces cytochrome c-dependent apoptosis in human promyelocytic leukaemia, HL-60 Cells. 1219 60

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
Leukemia 2002 Sep
PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 88

Boswellic acids are the compounds isolated from the gum resin of Boswellia serrata and have been used for the treatment of inflammatory diseases for many years in the countries of the east. Recently, a few studies showed that the acids may have anti-cancer effect on leukemia and brain tumours. We investigated the apoptotic and anti-proliferative effects of two types of boswellic acids, keto-beta-boswellic acid and acetyl-keto-beta-boswellic acid, on liver cancer Hep G2 cells. After treating the cells with the boswellic acids, cell proliferation, DNA synthesis, and apoptosis were analysed. The activities of caspase-3, -8 and -9 were assayed. To explore the apoptotic pathway, specific caspase inhibitors were employed. It was found that boswellic acids decreased cell viability and [3H]thymidine incorporation, checked the cells in the G1 phase, and increased percentage of sub-G1. Boswellic acids strongly induced apoptosis accompanied by activation of caspase-3, -8 and -9. The apoptosis was blocked completely by caspase-8 or caspase-3 inhibitor, but inhibited partly by caspase-9 inhibitor. However, these caspase inhibitors did not show any effect on the alternations of cell viability caused by boswellic acids. In conclusion, boswellic acids have anti-proliferation and anti-cancer effects on Hep G2 cells. The apoptotic effect is mediated by a pathway dependent on caspase-8 activation. The acids may be a promising drug for the chemoprevention of liver cancer.
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PMID:Keto- and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway. 1223 1

We have previously reported that in a MOLT-4 leukemia cell line the acquired resistance to 9-beta-D-arabinofuranosylguanine (Ara-G) is due to deficiency of the activating enzymes deoxyguanosine kinase and deoxycytidine kinase [Biochem. Biophys. Res. Commun. 293 (5) (2002) 1489]. In this study we investigated whether apoptotic pathways are affected in two human T-cell lymphoblastic MOLT-4 cell lines with acquired resistance to Ara-G. In contrast to the MOLT-4 wild type cells, Ara-G resistant cells displayed no increase in caspase-3 or caspase-9 activity, DNA fragmentation, cytochrome c release or a drop in the mitochondrial membrane potential (DeltaPsi(mito)) upon Ara-G treatment. A drop in the DeltaPsi(mito) was induced in wild type cells after treatment with tributyltin, an inducer of mitochondrial permeability transition, and with carbonyl cyanide m-chlorophenylhydrazone, an uncoupling agent that reduces the DeltaPsi(mito), although not in Ara-G resistant cells. Ara-G resistant cells displayed higher levels of the anti-apoptotic protein Bcl-xL in immunoblots. A recent study indicates that Ara-G-induced apoptosis is mediated in part via the Fas pathway [Cancer Res. 43 (2047) (2002) 411]. When cells were treated with anti-Fas antibody, the wild type cell line exhibited increased caspase-3-like activity but the Ara-G resistant cells did not. Using FACS analysis and semi-quantitative PCR, 3-6-fold decreased protein levels and almost no detectable mRNA levels of Fas in the resistant cells were recorded. These data indicate that the inability to induce apoptosis via both the apoptosome pathway and the Fas pathway, due to increased levels of Bcl-xL and a lack of Fas, contributes to Ara-G resistance. This resistance to apoptosis in Ara-G resistant cells may serve to explain the overall resistance to a variety of anti-neoplastic drugs.
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PMID:Resistance to mitochondrial- and Fas-mediated apoptosis in human leukemic cells with acquired resistance to 9-beta-D-arabinofuranosylguanosine. 1241 45

3-Iodoacetamido benzoyl ethyl ester (3-IAABE) is a new compound synthesized in our laboratory. The primary action of 3-IAABE is to inhibit microtubule assembly by interacting with -SH groups on tubulin. In contrast to other known microtubule disrupters, 3-IAABE caused a double blockade in the cell cycle at G(1)-S transition and in M phase. The blockade was determined by cell cycle analysis and chromosome distribution. Kinase activities of cyclin E and cyclin-dependent kinase 2 responsible for the G(1)-S transition were increased, as were the activities of mitotic cyclin B and cdc2. 3-IAABE treatment also increased p53 expression and dephosphorylated (or activated) retinoblastoma protein. Investigation of the signal transduction pathway showed that 3-IAABE induced bcl-2 phosphorylation, followed by activation of caspase-9, -3, and -6, but not caspase-8. DNA fragmentation factor and poly(ADP-ribose) polymerase, the downstream substrates of caspase-3 and -6, were cleaved after 3 h of exposure to 3-IAABE, followed by DNA fragmentation. Pretreatment of the cells with inhibitors of caspase-9, -3, or -6, respectively, inhibited the cleavage of DNA fragmentation factor and poly(ADP-ribose) polymerase and thus inhibited the onset of apoptosis. 3-IAABE showed antitumor activities in the panel of 60 National Cancer Institute human tumor cell lines with total growth inhibition in the range of 0.22-4.3 micro M for solid tumor lines and 0.025-0.22 micro M for leukemia/lymphoma cell lines. The 3-IAABU total growth inhibition of phytohemagglutinin-stimulated healthy human lymphocytes was 450-fold greater than that of leukemic cells. 3-IAABE significantly inhibited the growth of human hepatocarcinoma (BEL-7402) in nude mice by 72% in tumor volume, more strongly than did vincristine (43 percent inhibition). Besides being a novel lead for the design of new anticancer tubulin ligands, the activity of 3-IAABE in the cell cycle may also help us to understand the molecular pharmacology of microtubule-active drugs.
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PMID:Double blockade of cell cycle at g(1)-s transition and m phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. 1241 32

We have examined the effects of the CDK1 inhibitor CGP74514A on cell cycle- and apoptosis-related events in human leukemia cells. An 18-hr exposure to 5 microM CGP74514A induced mitochondrial damage (i.e., loss of Delta psi(m)) and apoptosis in multiple human leukemia cell lines (e.g., U937, HL-60, KG-1, CCRF-CEM, Raji, and THP; range 30-95%). In U937 cells, CGP74514A- induced apoptosis (5 microM) became apparent within 4 hr and approached 100% by 24 hr. The pan- caspase inhibitor Boc-fmk and the caspase-8 inhibitor lETD-fmk opposed CGP74514A-induced caspase-9 activation and PARP degradation, but not cytochrome c or Smac/DIABLO release. CGP74514A-mediated apoptosis was substantially blocked by ectopic expression of full-length Bel- 2, a loop-deleted mutant Bcl-2, and Bcl-x(L). CGP74514A treatment (5 microM; 18 hr) resulted in increased p21(CIP1) expression, p27(KIP1) degradation, diminished E2F1 expression, and dephosphorylation of p34(CDC2). It also induced early (i.e., within 2 hr) inhibition of CDK1 activity and dephosphorylation of pRb, followed by pRb degradation, but did not block pRb phosphorylation at CDK2- and CDK4- specific sites. These findings indicate that the selective CDK1 inhibitor, CGP74514A, induces complex changes in cell cycle-related proteins in human leukemia cells accompanied by extensive mitochondrial damage, caspase activation, and apoptosis.
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PMID:Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. 1242 20


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