naphthoquinones and beta-hydroxyisovalerylshikonin

Studies of the mechanism of action of a shikonin derivative, beta-hydroxyisovalerylshikonin (beta-HIVS), have revealed that beta-HIVS inhibits the protein tyrosine kinase (PTK) activities of the receptor for epidermal growth factor and v-Src. In this review, we compare the characteristics of the inhibition of PTK activity by beta-HIVS with those of other inhibitors of PTKs. The chemical structure of beta-HIVS is completely different from that of ATP and it does not resemble any of the PTK inhibitors reported to date, except that it includes the benzylidene moiety. In contrast to most PTK inhibitors, the mechanism of inhibition by beta-HIVS is non-competitive with respect to ATP, but competitive with respect to its peptide substrate. This feature of the mechanism of inhibition of PTK by beta-HIVS suggests that it might be useful in a clinical setting with other PTK inhibitors. When Bcr-Abl-positive, human leukemia K562 cells were treated simultaneously with beta-HIVS and STI571 (Gleevec), these compounds had a synergistic effect on both the induction of apoptosis in K562 cells and the inhibition of the phosphorylation activity of PTK, probably because the mechanism of interference with phosphorylation by beta-HIVS and the binding site of beta-HIVS are different from those of STI571.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; Benzamides; Drug Interactions; Humans; Imatinib Mesylate; K562 Cells; Naphthoquinones; Phosphorylation; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Structure-Activity Relationship

Osteoarthritis is a chronic degenerative disease characterized by cartilage destruction. It is the fourth most disabling disease worldwide and is currently incurable. Inflammation and extracellular matrix (ECM) degradation are considered to be substantial reasons for accelerating the progression of OA. β-Hydroxyisoamylshikonin (β-HIVS) is a natural naphthoquinone compound with anti-inflammatory and antioxidant activity. However, the effect of β-HIVS on OA is still unclear. In this study, we found that β-HIVS can down-regulate the expression of NO, PEG2, IL-6, TNF-α, COX-2, and iNOS, suggesting its anti-inflammatory effects in chondrocytes; we also found that β-HIVS may down-regulate the expression of ADAMTS5 and MMP13 and up-regulate the expression of aggrecan and collagen II to inhibit the degradation of ECM. Mechanistically, β-HIVS inhibited the NFκB pathway by activating the Nrf2/HO-1 axis, thereby exerting its anti-inflammatory and inhibitory effects on ECM degradation. In vivo experiments also proved the therapeutic effects of β-HIVS on OA in mice, and Nrf2 is the target of β-HIVS. These findings indicate that β-HIVS may become a new drug for the treatment of OA.

Topics: Animals; Anti-Inflammatory Agents; Chondrocytes; Heme Oxygenase-1; Humans; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Mice; Mice, Inbred C57BL; Naphthoquinones; NF-E2-Related Factor 2; NF-kappa B; Osteoarthritis

β-hydroxyisovalerylshikonin (β-HIVS), which is a natural naphthoquinone compound, is one of the main chemicals isolated from a therapeutic plant, Lithospermum erythrorhizon. In the present study, we demonstrated that β-HIVS inhibited the adipogenesis of 3T3-L1 cells through AMP-activated protein kinase (AMPK)-mediated modulation of sterol regulatory element binding protein (SREBP)‑1c. The anti-adipogenic effect of β-HIVS was accompanied by the increased phosphorylation of AMPK and precursor SREBP‑1c. In β-HIVS-treated 3T3-L1 cells, AMPK was activated and phosphorylated precursor SREBP‑1c, preventing the cleavage of precursor SREBP‑1c to mature SREBP‑1c. Expression of the fat-forming enzymes, acetyl-CoA carboxylase (ACC)1, fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD)1, which are transcribed by mature SREBP‑1c, were downregulated, resulting in reduced intracellular fat accumulation. The anti-adipogenic effect of β-HIVS was significantly attenuated by AMPK knockdown. Knockdown of AMPK using siRNA decreased the phosphorylation of precursor SREBP‑1c and increased the levels of mature SREBP. The levels of the fat-forming enzymes, ACC1, FAS and SCD1, as well as intracellular fat accumulation were also significantly increased by AMPK knockdown. These results suggest that β-HIVS activated AMPK, which was followed by the downregulation of mature SREBP‑1c and fat-forming enzymes, leading to the inhibition of adipogenesis.

Topics: 3T3-L1 Cells; Acetyl-CoA Carboxylase; Aldehyde Oxidoreductases; AMP-Activated Protein Kinases; Animals; Cell Survival; Mice; Naphthoquinones; Reverse Transcriptase Polymerase Chain Reaction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1

In the present study, we investigated whether β-hydroxyisovalerylshikonin (β-HIVS) affects the production of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in BV2 microglial cells. Our data showed that β-HIVS inhibited secretion of NO and PGE2 and downregulated expression of their main regulatory genes, inducible NO synthesis (iNOS) and cyclooxygenase-2 (COX-2). β-HIVS also reduced the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) by suppressing nuclear translocation of the NF-κB subunits and inhibiting the degradation and phosphorylation of IκBα. Furthermore, an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), attenuated LPS-stimulated iNOS and COX-2 expression, suggesting that NF-κB inhibition is a main effector in the expression of iNOS and COX-2. We also found that LPS-induced NF-κB activation is regulated through inhibition of PI3K/Akt phosphorylation in response to β-HIVS. Additionally, β-HIVS caused the induction of heme oxygenase-1 (HO-1) via upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2), both of which are involved in the secretion of proinflammatory mediators such as NO and PGE2. Taken together, our data indicate that β-HIVS diminishes the proinflammatory mediators NO and PGE2 and the expression of their regulatory genes, iNOS and COX-2, in LPS-stimulated BV2 microglial cells by inhibiting PI3K/Akt-dependent NF-κB activation and inducing Nrf2-mediated HO-1 expression.

Topics: Animals; Cell Line; Dinoprostone; Heme Oxygenase-1; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Mice; Microglia; Molecular Structure; Naphthoquinones; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrrolidines; Thiocarbamates

A series of novel β-hydroxyisovalerylshikonin analogues bearing oxygen-containing substituents at the side-chain hydroxyl of shikonin were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against multi-drug resistant (MDR) cell lines DU-145 and HeLa. Most compounds exhibited significant inhibitory activity on both cell lines. The structure-activity relationship showed the analogues with ether substituents displayed the most potent antitumour activity and selective cytotoxicity towards DU-145. Among the compounds with ether substituents, increasing the steric hindrance in the carbon bearing β-hydroxyl or replace the β-hydroxyl with acetoxy or methoxy would lead to the decline of cytotoxicity.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Naphthoquinones; Structure-Activity Relationship

Shikonin and beta-hydroxyisovalerylshikonin (beta-HIVS) from Lithospermum erythrorhizon inhibit angiogenesis via inhibition of vascular endothelial growth factor receptors (VEGFR) in an adenosine triphosphate-non-competitive manner, although the underlying molecular mechanism has not been fully understood. In the present study, we found that beta-HIVS inhibited angiogenesis within chicken chorioallantoic membrane approximately threefold more efficiently than shikonin. beta-HIVS also significantly inhibited angiogenesis in two other assays, induced either by Lewis lung carcinoma cells implanted in mouse dorsal skin or by VEGF in s.c. implanted Matrigel plugs and metastasis of Lewis lung carcinoma cells to lung. Therefore, using beta-HIVS as a bioprobe, we investigated the molecular mechanism of shikonin's anti-angiogenic actions. beta-HIVS inhibited the phosphorylation and expression of VEGFR2 and Tie2 without affecting VEGFR1 and fibroblast growth factor receptor 1 levels. beta-HIVS suppressed the phosphorylation but not the expression of extracellular signal-regulated kinase, and an Sp1-dependent transactivation of the VEGFR2 and Tie2 promoters, thereby suppressing the proliferation of vascular endothelial and progenitor cells. This was mimicked by an Sp1 inhibitor mithramycin A and partially rescued by Sp1 overexpression. These results implicate potential use of shikonin and beta-HIVS as leading compounds for clinical application in the future by virtue of their unique properties including: (i) inhibition of VEGFR2 and Tie2 phosphorylation in an adenosine triphosphate-non-competitive manner; (ii) simultaneous inhibition of the phosphorylation and expression of VEGFR2 and Tie2; and (iii) bifunctional inhibition of the growth in endothelial cells and vascular remodeling.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Carcinoma, Lewis Lung; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Chickens; Chorioallantoic Membrane; Drugs, Chinese Herbal; Electrophoretic Mobility Shift Assay; Female; Immunoenzyme Techniques; Immunoprecipitation; Luciferases; Mice; Mice, Inbred C57BL; Naphthoquinones; Neovascularization, Pathologic; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transfection; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Apoptotic cell death was induced in human lung cancer DMS114 cells by treatment with beta-hydroxyisovalerylshikonin (beta-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases. Changes in phosphoprotein profiles were analyzed by two-dimensional-polyacrylamide gel electrophoresis (2D-PAGE) after the cells were treated with beta-HIVS. One spot on the 2D gel showed a marked decrease in intensity and the corresponding protein was identified by mass spectrometry as dUTP nucleotidohydrolase (dUTPase). The beta-HIVS-induced decrease of dUTPase in the phosphoprotein fraction of DMS114 cells was confirmed using immunoblotting. Treatment of the cells with beta-HIVS-induced rapid reduction of dUTPase activity. An antioxidant N-acetyl-cysteine inhibited both the reduction of phosphorylated dUTPase and the induction of apoptosis by beta-HIVS treatment of DMS114 cells. Introduction of siRNA directed against dUTPase mRNA into DMS114 cells enhanced the susceptibility of beta-HIVS-induced apoptosis. Treatment of DMS114 cells with beta-HIVS and 5-fluorouracil, a specific inhibitor of thymidylate synthase used as a chemotherapeutic drug, revealed the synergistic effects of these drugs on the inhibition of cell growth. These results suggest that dUTPase activity is one of the crucial factors involved in apoptotic cell death in lung cancer cells.

Topics: Amino Acid Sequence; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Proliferation; Deoxyuracil Nucleotides; Enzyme Activation; Fluorouracil; Humans; Lung Neoplasms; Molecular Sequence Data; Naphthoquinones; Phosphoproteins; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrophosphatases; RNA, Small Interfering

Beta-hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in some lines of human tumor cells. We investigated the effect of beta-HIVS on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells.. Endometrial and ovarian cancer cells were treated with various concentrations of beta-HIVS, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated.. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of beta-HIVS, although normal endometrial epithelial cells were viable after treatment with the same doses of beta-HIVS that induced growth inhibition in endometrial and ovarian cancer cells. Cell-cycle analysis indicated that their exposure to beta-HIVS decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis.. These results suggest that the anticancer activity of beta-HIVS may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that beta-HIVS may become a useful adjuvant therapy for endometrial and ovarian cancers.

Topics: Apoptosis; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Endometrial Neoplasms; Female; Humans; Intracellular Signaling Peptides and Proteins; Membrane Potential, Mitochondrial; Naphthoquinones; Ovarian Neoplasms; Up-Regulation

Most of the current medical treatments for endometriosis aim to down-regulate the estrogen activity. However, a high recurrence rate after medical treatments has been the most significant problem. Beta-hydroxyisovalerylshikonin (beta-HIVS) is an ATP non-competitive inhibitor of protein-tyrosine kinases and is considered an apoptosis-inducing agent. The aim of this study is to evaluate the effects of beta-HIVS on the proliferation, cell cycle and apoptosis of endometriotic stromal cells.. We investigated the effects of beta-HIVS on cultured ovarian endometriotic cyst stromal cells (ECSC) by a modified methylthiazoletetrazolium (MTT) assay, a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and internucleosomal DNA fragmentation assays. The effect of beta-HIVS on the cell cycle of ECSC was determined by flow cytometry. The expression of apoptosis-related molecules was examined in ECSC using western blot analysis.. Beta-HIVS significantly inhibited the proliferation and DNA synthesis of ECSC and induced apoptosis and G0/G1 phase cell-cycle arrest of these cells. Down-regulation of the B-cell lymphoma/leukaemia-2 (Bcl-2) expression with the activation of caspase-3, caspase-8 and caspase-9 was observed in ECSC after beta-HIVS treatment.. These results suggest that beta-HIVS induces apoptosis of ECSC by suppressing anti-apoptotic proteins. Although our present findings are preliminary, beta-HIVS could potentially be a therapeutic agent for the treatment of endometriosis.

Topics: Apoptosis; Bromodeoxyuridine; Cell Cycle; Cell Division; Cell Survival; DNA Fragmentation; Endometriosis; Female; G1 Phase; G2 Phase; Humans; In Vitro Techniques; Naphthoquinones; Premenopause; Resting Phase, Cell Cycle; S Phase; Stromal Cells

beta-Hydroxyisovalerylshikonin (beta-HIVS) and cisplatin (CDDP) had a synergistic growth-inhibitory effect on cultured human small-cell lung carcinoma DMS114 cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells, while beta-HIVS and CDDP alone at the same respective concentrations had little effect. Growth inhibition was accompanied by induction of apoptosis, as determined by an ELISA for the detection of cell death and the TUNEL assay. Using phosphotyrosine-specific antibodies (PY20), we observed that tyrosine kinase activity in DMS114 cells was inhibited by treatment with beta-HIVS and CDDP together. The tyrosine kinase activity of isolated Src and that of isolated receptors for epidermal growth factor were also inhibited by the two agents together. The synergistic effects of the growth of DMS114 cells of beta-HIVS and CDDP were not due simply to the intracellular accumulation of CDDP or to levels of DNA adducts. Our data suggest that the synergistic effect on the growth of DMS114 cells of beta-HIVS and CDDP might be a result of the inhibition of a tyrosine kinase-dependent pathway.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cisplatin; Drug Synergism; Humans; In Situ Nick-End Labeling; Lung Neoplasms; Naphthoquinones; Protein-Tyrosine Kinases; Tumor Cells, Cultured

beta-Hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in various lines of human tumor cells. However, the way in which beta-HIVS induces apoptosis remains to be clarified. In this study, we performed cDNA array analysis and found that beta-HIVS suppressed the expression of the gene for tumor necrosis factor receptor-associated protein 1 (TRAP1), which is a member of the heat-shock family of proteins. When human leukemia HL60 cells and human lung cancer DMS114 cells were treated with beta-HIVS, the amount of TRAP1 in mitochondria decreased in a time-dependent manner during apoptosis. A similar reduction in the level of TRAP1 was also observed upon exposure of cells to VP16. Treatment of DMS114 cells with TRAP1-specific siRNA sensitized the cells to beta-HIVS-induced apoptosis. Moreover, the reduction in the level of expression of TRAP1 by TRAP1-specific siRNA enhanced the release of cytochrome c from mitochondria when DMS114 cells were treated with either beta-HIVS or VP16. The suppression of the level of TRAP1 by either beta-HIVS or VP16 was blocked by N-acetyl-cysteine, indicating the involvement of reactive oxygen species (ROS) in the regulation of the expression of TRAP1. These results suggest that suppression of the expression of TRAP1 in mitochondria might play an important role in the induction of apoptosis caused via formation of ROS.

Topics: Acetylcysteine; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Blotting, Northern; Blotting, Western; Cell Death; Cell Line; Cell Line, Tumor; Coloring Agents; Cytochromes c; Cytosol; DNA, Complementary; Dose-Response Relationship, Drug; Enzyme Inhibitors; Etoposide; Gene Expression Regulation; Genetic Vectors; HL-60 Cells; HSP90 Heat-Shock Proteins; Humans; K562 Cells; Mitochondria; Naphthoquinones; Oligonucleotide Array Sequence Analysis; Plasmids; Reactive Oxygen Species; RNA, Small Interfering; Subcellular Fractions; Time Factors; Transfection

beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermum radix, induces apoptosis in various lines of human tumor cells. To identify genes involved in beta-HIVS-induced apoptotic process, we performed cDNA array analysis and found that beta-HIVS suppresses the expression of the gene for a polo-like kinase 1 (PLK1) that is involved in control of the cell cycle. When U937 and HL60 cells were treated with 10(-6) M beta-HIVS for 0.5 h, both the amount of PLK1 itself and the kinase activity of this enzyme were decreased. By contrast, Bcr-Abl-positive K562 cells were resistant to the induction of apoptosis by beta-HIVS and this compound did not suppress the kinase activity of PLK1 in these cells. However, simultaneous treatment of K562 cells with both beta-HIVS and STI571, which selectively inhibits the protein tyrosine kinase (PTK) activity of Bcr-Abl, strongly induced apoptosis. Moreover, beta-HIVS increased the inhibitory effect of STI571 on PTK activity. Treatment of K562 cells with antisense oligodeoxynucleotides (ODNs) specific for PLK1 sensitized these cells to the beta-HIVS-induced fragmentation of DNA. These results suggest that suppression of the activity of PLK1 via inhibition of tyrosine kinase activity by beta-HIVS might play a critical role in the induction of apoptosis.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzamides; Cell Cycle Proteins; Cell Line; Cysteine Proteinase Inhibitors; DNA, Complementary; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genistein; HL-60 Cells; Humans; Imatinib Mesylate; K562 Cells; Kidney; Leukemia, Myeloid; Naphthoquinones; Neoplasm Proteins; Oligodeoxyribonucleotides, Antisense; Oligonucleotide Array Sequence Analysis; Phosphorylation; Piperazines; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Kinases; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; U937 Cells

Treatment of human epidermoid carcinoma A431 cells with transplatin (trans-DDP) and beta-hydroxyisovalerylshikon (beta-HIVS) together had a strong inhibitory effect on A431 cells. By contrast, trans-DDP and beta-HIVS by themselves, at the same respective concentrations, had practically no effect. The tyrosine kinase activities of v-Src and epidermal growth factor (EGFR) were inhibited by each of the two agents alone and strongly inhibited by combination. The observed synergistic inhibitory effect on the growth of A431 cells might have resulted from the inhibition of EGFR by trans-DDP, as well as by beta-HIVS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Synergism; ErbB Receptors; Humans; Naphthoquinones; Oncogene Protein pp60(v-src); Phosphorylation; Tumor Cells, Cultured; Tyrosine

Beta-hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from Lithospermium radix, most efficiently induced cell-death in two lines of lung cancer cells, namely, NCI-H522 and DMS114, whereas shikonin was effective against a wide variety of tumor cell lines. During our studies of the mechanism of action of beta-HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v-Src were strongly inhibited and that of KDR/Flk-1 was weakly inhibited by beta-HIVS. The inhibition by beta-HIVS of the activities of EGFR and v-Src was much stronger than that by shikonin. The IC50 values of beta-HIVS for EGFR and v-Src were approximately 0.7 microM and 1 microM, respectively. Moreover, the inhibition of v-Src by beta-HIVS was non-competitive with respect to ATP. These results strongly suggest that the action of beta-HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound.

Topics: 3T3 Cells; Adenosine Triphosphate; Animals; Antineoplastic Agents, Phytogenic; Cell Death; Dose-Response Relationship, Drug; Enzyme Inhibitors; ErbB Receptors; Humans; Inhibitory Concentration 50; Kinetics; Mice; Models, Chemical; Naphthoquinones; Protein-Tyrosine Kinases; Tumor Cells, Cultured

beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermium radix, inhibited the growth of various lines of cancer cells derived from human solid tumors at low concentrations between 10(-8) and 10(-6) M. When HL-60 cells were treated with 10(-6) M beta-HIVS for 3 h, characteristic features of apoptosis, such as DNA fragmentation, nuclear fragmentation, and activation of caspase-3-like activity, were observed. The most characteristic features of the effect of beta-HIVS were the remarkable morphological changes induced upon treatment of HL-60 cells with beta-HIVS, as visualized on the staining of actin filaments with phalloidin labeled with tetramethylrhodamine B isothiocyanate. Moreover, activation of MAP kinases, such as ERK2, JNK and p38, was detected after treatment with 10(-6) M beta-HIVS preceding the appearance of the characteristics of apoptosis, and the features of the activation of these MAP kinases were quite different from those of Fas and anticancer drug-induced apoptosis. The activation of JNK by beta-HIVS was not inhibited by inhibitors of caspases, suggesting that JNK is located either upstream or independent of the caspase signaling pathway. beta-HIVS did not inhibit the activity of topoisomerase II. These results indicate that beta-HIVS induces apoptosis in HL-60 cells through a mechanism unlike those reported for anti-Fas antibodies and etoposide.

Topics: Antineoplastic Agents; Apoptosis; Calcium-Calmodulin-Dependent Protein Kinases; Caspase 3; Caspases; Cell Division; DNA Fragmentation; Drug Screening Assays, Antitumor; Enzyme Activation; Etoposide; fas Receptor; HL-60 Cells; Humans; Naphthoquinones; Nucleic Acid Synthesis Inhibitors; Signal Transduction; Tumor Cells, Cultured