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)

Eleven known compounds and a new prenylated naphthoquinone, lippsidoquinone (13), were isolated from ethanol extracts of Lippia sidoides. Their structures were established by a combination of 1D and 2D NMR, IR, and EIMS spectral data analysis. The cytotoxic properties of compounds 3--13 were evaluated against HL60, SW1573, and CEM cell lines. Only tectol (6) and lippsidoquinone (13) exhibited significant activity against human leukemia cell lines HL60 and CEM.
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PMID:Chemical constituents from Lippia sidoides and cytotoxic activity. 1142 46

beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.
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PMID:[Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use]. 1147 85

To explore the relationship between the susceptibility to arsenic trioxide (As(2)O(3))-induced apoptosis of leukemia cells and the level of reactive oxygen species (ROS) of cells, flow cytometry and electron microscopy were applied to identify apoptosis, and dihydrorhodamine123 was used to display the ROS level of cells. As(2)O(3) alone or in combination with 2,3-dimethoxy-1,4-naphthoquinone (DMNQ, 2.5 &mgr;mol/L for NB4 cells, 10 &mgr;mol/L for U937 cells) were used to induce cell apoptosis. The results showed that NB4 cells possessed higher level of ROS than U937 cells. DMNQ raised ROS levels of NB4 and U937 cells, sensitized U937 cells to As(2)O(3)-induced apoptosis, and enhanced the efficacy of As(2)O(3)-induced apoptosis of NB4 cells. Catalase reversed the effect of DMNQ on NB4 and U937 cells. It was concluded that the susceptibility of leukemia cells to arsenic trioxide-induced apoptosis is determined by ROS level in the cells.
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PMID:The Susceptibility of Leukemia Cells to Arsenic Trioxide-induced Apoptosis is Determined by Cellular Reactive Oxygen Species Level. 1204 Apr 5

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess pronounced antifungal profile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover 7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.
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PMID:Design, synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antifungal and anticancer agents. 1498 Jun 39

The synthesis and evaluation of some 2-substituted-1,4-naphthoquinones 2, S-(1,4-naphthoquinon-2-yl)-mercaptoalkanoic acid amides 4, related benzoquinone and naphthoquinone derivatives 6-9 and 2,3-disubstituted 1,4-naphthoquinones 10-11 were carried out. The antifungal, antibacterial, antiviral and anticancer activities were determined by using the standard assay. The results show that compounds 2b and 10a showed in vitro antiviral activity against Influenza-A Virus and Herpes Simplex Virus and possess pronounced antifungal profile whereas 4a showed anticancer activities against Lymphoid Leukaemia P 388.
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PMID:Synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antiviral, antifungal and anticancer agents. 1512 56

Cellular oxidation/reduction state affects the cytotoxicity of a number of chemotherapeutic agents, including arsenic trioxide. Reactive oxygen species (ROS), the major intracellular oxidants, may be a determinant of cellular susceptibility to arsenic. Our previous studies showed that a naphthoquinone and an anthraquinone (emodin) displayed the capability of producing ROS and facilitating arsenic cytotoxicity in both leukemia and solid tumor cell lines. We therefore attempted to test emodin and several other kinds of anthraquinone derivatives on EC/CUHK1, a cell line derived from esophageal carcinoma, and on a nude mouse model, with regard to their effects and mechanisms. Results showed that anthraquinones could produce ROS and sensitize tumor cells to arsenic both in vivo and in vitro. The combination of emodin and arsenic promoted the major apoptotic signaling events, i.e., the collapse of the mitochondrial transmembrane potential, the release of cytochrome c, and the activation of caspases 9 and 3. Meanwhile a combination of emodin and arsenic suppressed the activation of transcription factor NF-kappaB and downregulated the expression of a NF-kappaB-specific antiapoptotic protein, survivin. These two aspects could be antagonized by the antioxidant N-acetyl-L-cysteine. Therefore anthraquinones exert their effects via a ROS-mediated dual regulation, i.e., the enhancement of proapoptosis and the simultaneous inhibition of antiapoptosis. In vivo study showed that emodin made the EC/CUHK1 cell-derived tumors more sensitive to arsenic trioxide with no additional systemic toxicity and side effects. Taken together, these results suggest an innovative and safe chemotherapeutic strategy that uses natural anthraquinone derivatives as ROS generators to increase the susceptibility of tumor cells to cytotoxic therapeutic agents.
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PMID:Anthraquinones sensitize tumor cells to arsenic cytotoxicity in vitro and in vivo via reactive oxygen species-mediated dual regulation of apoptosis. 1554 21

6-(1-Hydroxyimino-4-methylpentyl)5,8-dimethyoxy 1,4-naphthoquinone S-52 (DMNQ S-52) was reported to have cytotoxic activity against L1210 leukemia cells. In the present study, we investigated the apoptotic mechanism of DMNQ S-52 in vitro and in vivo in murine solid cancer cells. DMNQ S-52 exerted cytotoxicity against Lewis lung carcinoma (LLC) cells (IC50=12.3 microM). DMNQ S-52 increased Annexin V positive cell population in a concentration-dependent manner. DMNQ S-52 also induced apoptosis through caspase-mediated pathway, including activation of caspase-3, cleavage of Poly(ADP-ribose) polymerase (PARP) and decreased expression of Bcl-2 in LLC cells in a time and concentration-dependent fashion. DMNQ S-52 activated the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 as well as abrogated the expression of extracellular signal-regulated kinase (ERK) in a time-dependent manner at 10 microM. Similarly, cell proliferation inhibition by DMNQ S-52 was masked by caspase inhibitor Z-Asp-Glu-Val-Asp-fluoromethylketone (Z-VAD-FMK), JNK inhibitor SP600125 and p38 inhibitor SB203580, but not by MEK inhibitor U0126. Furthermore, i.p. administration of DMNQ S-52 at 5 mg/kg resulted in a potent inhibition of the growth of LLC cells implanted on the right flank of C57BL/6 mice compared to untreated control. Immunohistochemical analysis revealed the decreased tumor cell proliferation and increased tumor cell apoptosis in DMNQ S-52 treated tumor sections using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and proliferation cell nuclear antigen (PCNA). Taken together, these findings demonstrate that DMNQ S-52 may exhibit anti-tumor activity by inducing apoptosis via caspases and mitogen activated protein (MAP) kinase-dependent pathways.
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PMID:MAPK regulation and caspase activation are required in DMNQ S-52 induced apoptosis in Lewis lung carcinoma cells. 1589 20

1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC(50) value of 7.75 microM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC(50) value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development.
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PMID:SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. 1657 Feb 88

Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In this study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C(1) and C(4) of shikonin potentially interact with the catalytic site of beta 5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC(50) 12.5 micromol/L) and tumor cellular 26S proteasome (IC(50) between 2-16 micromol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (I kappaB-alpha, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin and inhibition of the proteasome activity by shikonin contributes to its antitumor property.
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PMID:Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. 1916 59

(+)-Cordiaquinone J is a 1,4-naphthoquinone isolated from the roots of Cordia leucocephala that has antifungal and larvicidal effects. However, the cytotoxic effects of (+)-cordiaquinone J have never being explored. In the present study, the effect of (+)-cordiaquinone J on tumor cells viability was investigated, showing IC(50) values in the range of 2.7-6.6muM in HL-60 and SF-295 cells, respectively. Studies performed in HL-60 leukemia cells indicated that (+)-cordiaquinone J (1.5 and 3.0muM) reduces cell viability and 5-bromo-2-deoxyuridine incorporation after 24h of incubation. (+)-Cordiaquinone J showed rapid induction of apoptosis, as indicated by phosphatidylserine externalization, caspase activation, DNA fragmentation, morphologic changes, and rapid induction of necrosis, as indicated by the loss of membrane integrity and morphologic changes. (+)-Cordiaquinone J altered the redox potential of cells by inducing the depletion of reduced GSH intracellular content, the generation of reactive oxygen species and the loss of mitochondrial membrane potential. However, pre-treatment of cells with N-acetyl-l-cysteine abolished most of the observed effects related to (+)-cordiaquinone J treatment, including those involving apoptosis and necrosis induction.
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PMID:Oxidative stress induction by (+)-cordiaquinone J triggers both mitochondria-dependent apoptosis and necrosis in leukemia cells. 1996 71


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