naphthoquinones and Fibrosarcoma

Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our MFS cellular model of tumor heterogeneity for developing a new therapeutic approach. The impact of shikonin and β,β-dimethylacrylshikonin (DMAS) on viability, apoptotic induction, MAPK phosphorylation, and DNA damage response were analyzed by means of two human MFS cell lines, MUG-Myx2a and MUG-Myx2b, derived from a singular tumor tissue specimen. MFS cells showed a dose-dependent inhibition of cell viability and a significant induction of apoptosis. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase in pAKT, pERK, pJNK, and pp38. DMAS and shikonin inhibited the activation of the two master upstream regulators of the DNA damage response, ATR and ATM. MUG-Myx2b, which contains an additional

Topics: Adult; Apoptosis; Cell Line, Tumor; Fibrosarcoma; Humans; Naphthoquinones; Signal Transduction

Anti-cancer effect of lapachol contained in Tabebuia avellandae has been poorly understood until now.. The aim of this study was to investigate the inhibitory effect of lapachol on MMPs related to cell invasion. Its action mechanism was elucidated by analyzing the activity and the expression of MMPs and the proteins involved in the signaling pathway of cell invasion.. The cytotoxicity of lapachol was evaluated by MTT assay in HT1080 cells. The effects of lapachol on the expression and the activation of MMPs were analyzed by western blot, immunofluorescence staining, and gelatin zymography assays. Their gene expression was analyzed by RT-PCR, and metastasis was evaluated by cell invasion assay.. Lapachol below 2 μM showed no cytotoxicity. It was observed that lapachol above 0.5 μM inhibited the activation of MMP-2 and MMP-9 stimulated by PMA. In particular, the protein and gene expression levels of MMP-2 stimulated by PMA were remarkably decreased in the presence of lapachol at 1 μM compared with the PMA treatment group. In addition, lapachol increased the expression level of TIMP-1 compared with the PMA treatment group. Moreover, lapachol decreased the expression level of p-p38 among MAPKs compared with the PMA treatment group. It was also found that the expression level of p65, a part of NF-kB, in nuclei was reduced in the presence of lapachol above 0.5 μM compared with the PMA treatment group. In addition, lapachol inhibited the invasion of human fibrosarcoma cells stimulated with VEGF.. Above results suggest that lapachol could play an important role in the modulation of MMPs related to cell invasion via the increase in TIMP-1 expression as well as the inactivation of p38 through NF-kB transcription factor.

Topics: Cell Line, Tumor; Fibrosarcoma; Humans; Matrix Metalloproteinases; Naphthoquinones; NF-kappa B

Phytochemical studies of the roots and aerial parts of endemic Arnebia purpurea S. Erik & H. Sumbul resulted in the isolation and characterization of four naphthoquinones [isovalerylalkannin (1), α-methyl-n-butanoyl alkannin (2), acetylalkannin (3), and alkannin (4)], a triterpene derivative [3-O-acetyl-oleanolic acid (5)], a steroid [β-sitosterol (6)], three flavonoid glycosides [isorhamnetin-3-O-rutinoside (7), kaempferol-3-O-rutinoside (8), kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside (9)] and a phenolic acid [rosmarinic acid (10)]. 3-O-Acetyl-oleanolic acid, isorhamnetin-3-O-rutinoside, kaempferol-3-O-mrutinoside, and kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside are reported from an Arnebia species for the first time. Cytotoxic activities on L929 murine fibrosarcoma cell line of the isolated compounds were investigated using MTT assay. Naphthoquinones (1-4) showed intermediate cytotoxic activity in comparison with the standard, doxorubicin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Boraginaceae; Cell Line, Tumor; Fibrosarcoma; Mice; Naphthoquinones; Plant Components, Aerial; Plant Roots

Bio-reduction/activation of anti-cancer drug beta-lapachone (beta-lap) is mediated by NAD(P)H: Quinone oxidoreductase (NQO1). We investigated the feasibility of using mild temperature hyperthermia to increase the anti-cancer effect of beta-lap by up-regulating NQO1 expression.. NQO1 expression in FSaII fibrosarcoma of C3H mice and A549 human lung cancer cells was evaluated with Western blot analysis and immunostaining of cells at different times after water-bath heating. Clonogenic cell survival method was used to determine the sensitivity of cells to heating, beta-lap, and in combination. The growth of FSaII tumors in the right hind legs of C3H mice was studied after heating the tumors at 42 degrees C for 1 h with water bath, an i.p. injection of beta-lap to host mice or an i.p. injection of beta-lap 24 h after heating the tumors.. Heating at 42 degrees C for 1 h significantly increased the expression of NQO1 in the cancer cells with a maximum increase occurring 8-24 h after heating. The sensitivity of cancer cells to beta-lap treatment progressively increased until 24 h after heating most likely due to the increase in NQO1 expression. Heating the FSaII tumors at 42 degrees C for 1 h and treating the host mice with an i.p. injection of 50 mg/kg beta-lap 24 h after the tumor heating was far more effective than heating alone or beta-lap treatment alone to suppress the tumor growth.. Mild temperature heat shock elevates the NQO1 expression in cancer cells, which in turn markedly increases the sensitivity of the cells to the bioreductive drug beta-lap in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Fibrosarcoma; Humans; Hyperthermia, Induced; Lung Neoplasms; Mice; NAD(P)H Dehydrogenase (Quinone); NADPH Dehydrogenase; Naphthoquinones; Neoadjuvant Therapy; Temperature

Radio-resistance in tumor cells and associated escape from apoptotic mechanism is a major problem in clinical cancer radiotherapy. Therefore, as a strategy to enhance the apoptosis, a combination of radiation and tumor-selective cytotoxic agents might improve the efficacy of treatment. Thus, the radiomodifying potential of diospyrin diethylether (D7), a plant-derived antitumor agent, was studied in fibrosarcoma tumor, both in vitro and in vivo.. Mouse and human fibrosarcoma (Wehi164; HT1080) cells were treated with D7, alone, or in combination with radiation, for determination of cytotoxicity, clonogenic survival, and apoptotic death assays. Involvement of oxidative mechanism and nuclear factor kappa B (NF-kappaB) was studied in different treatment groups. In addition, fibrosarcoma-bearing mice were treated with D7 (intravenously, two doses, each of 1 mg/kg body weight) combined with radiation (two fractions of 2.5 Gy each) at appropriate intervals. The tumor volume was measured to assess 'tumor growth delay', and liver function enzymes in the serum of mice were estimated after the treatments.. A combination treatment with D7 and radiation showed enhancement in cytotoxicity and apoptotic induction and decrease in clonogenic survival of tumor cells, as compared to the treatments with the drug or radiation alone. Moreover, D7 in combination with radiation could significantly inhibit the radiation-induced NF-kappaB activation, and showed the generation of comparatively more intracellular reactive oxygen species (ROS). Similarly, a combination of D7 and radiation in vivo caused significant inhibition of tumor growth in vivo, and restoring the liver enzyme activity to the 'normal' level.. The combined treatment with quinonoid D7 and radiation caused increased cytotoxicity compared to single treatment with either agent alone in fibrosarcoma tumor systems, both in vitro and in vivo.

Topics: Animals; Apoptosis; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Radiation; Fibrosarcoma; Humans; Mice; Naphthoquinones; NF-kappa B; Radiation Tolerance; Radiation-Sensitizing Agents; Reactive Oxygen Species

In our previous study, a synthetic benz[f]indole-4,9-dione analog, 2-amino-3-ethoxycarbonyl-N-methylbenz[f]indole-4,9-dione (SME-6), exhibited a potential anti-tumor activity. We, in this study, further explored the anti-metastatic and anti-invasive effect of SME-6 by determining the regulation of matrix metalloproteinases (MMPs). MMPs, zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. On this line, we examined the influence of SME-6 on the expressions of MMP-2, -9, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1, -2), and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent suppressions of MMPs and TIMP-2 mRNA levels were observed in SME-6-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. TIMP-1 mRNA level, however, was induced in a dose-dependent manner. Gelatin zymographic analysis also exhibited a significant down-regulation of MMP-2 and -9 expression in HT1080 cells treated with SME-6 compared to controls. Furthermore, SME-6 inhibited the invasion, motility, and migration of tumor cells. Taken together, these data provide a possible role of SME-6 as a potential antitumor agent with the markedly inhibition of the metastatic and invasive capacity of malignant cells.

Topics: Cell Line, Tumor; Cell Movement; Collagenases; Dose-Response Relationship, Drug; Down-Regulation; Fibrosarcoma; Humans; Imidazoles; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Naphthoquinones; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

Diosquinone [1], a naphthoquinone epoxide previously isolated from the root bark of Diospyros mespiliformis (Hostch) and D. tricolor [Ebenaceae] is been assessed for cytotoxicity activity against ten cancer cell lines by standard NIH method. The ethno-pharmacological claim of this plant and the previously observed good antibacterial activity of this compound among the others isolated from this plant suggest its probable cytotoxicity activity. Diosquinone was observed to be very active against most of the cancer cell lines. It shows very good activity against all the cell lines tested with ED50 value ranging between 0.18 microg/ml. against Human Glioblastoma (U373) to 4.5 microg/ml. against Hormone dependent human prostrate cancer( LNCaP).

Topics: Antineoplastic Agents; Breast Neoplasms; Colonic Neoplasms; Diospyros; Drug Resistance, Multiple; Female; Fibrosarcoma; Humans; Lung Neoplasms; Male; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms, Hormone-Dependent; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Tumor Cells, Cultured

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents, Phytogenic; Bacteria; Drug Evaluation, Preclinical; Female; Fibrosarcoma; Fungi; Leukemia, Experimental; Male; Mice; Naphthoquinones; Neoplasms, Experimental

Topics: Animals; Animals, Newborn; Carcinogens; Carcinoma, Hepatocellular; Dogs; Female; Fibroma; Fibrosarcoma; Granuloma; Hydroxylation; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Mice; Naphthalenes; Naphthoquinones; Neoplasms, Experimental; Nitroso Compounds; Urinary Bladder Neoplasms; Urine