naphthoquinones and Skin-Neoplasms

Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity.. This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy naïve subjects were treated with YM155 at a dose of 4.8 mg/m(2)/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression.. One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3-2.7). Median overall survival was 9.9 months (95% CI; 7.0-14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions.. YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Male; Melanoma; Microtubule-Associated Proteins; Middle Aged; Naphthoquinones; Neoplasm Staging; Skin Neoplasms; Survivin; Treatment Outcome

Eleven cases of patients bearing basic cellular carcinoma, and one case of patient bearing Kaposi's sarcomatosis, all treated with antibiotics isolated by Goncalves de Lima and Co-workers at the Instituto de Antibióticos, are presented by the authors. Primin, an antibiotic extracted from a vegetal named Miconia sp. (Herb. I.A.-1903) with a 2-metoxi-6-n-pentil-p benzoquinone structure, presented a strong antineoplastic action in the cases treated. Plumbagin isolated from Plumbago scandens in local use, was responsible for a complete healing of the injuries treated. Maytenin extracted from Maytenus sp. (Herb. I.A.-1750) showed less activity than the two previous mentioned, but with a low irritant action and late antineoplastic properties. The authors are going on these experiments. They believe that these antibodies, in local use, may advantageously substitute the surgery and the radiotherapy, meanly in those external ear tumidities and back of the nose, owing to a hurtful action in cartilage, provoked by radiotherapy.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Carcinoma, Basal Cell; Child; Clinical Trials as Topic; Drug Evaluation; Facial Neoplasms; Female; Humans; Male; Middle Aged; Naphthoquinones; Ointments; Quinones; Sarcoma, Kaposi; Skin Neoplasms

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC

Topics: Apoptosis; Azetidines; Cell Line; Humans; Melanoma; Naphthoquinones; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Plumbagin, a naphthoquinone extracted from the officinal leadwort presenting promising anti-cancer properties, has its therapeutic potential limited by its inability to reach tumors in a specific way at a therapeutic concentration following systemic injection. The purpose of this study is to assess whether a novel tumor-targeted, lipid-polymer hybrid nanoparticle formulation of plumbagin would suppress the growth of B16-F10 melanoma in vitro and in vivo.. Novel lipid-polymer hybrid nanoparticles entrapping plumbagin and conjugated with transferrin, whose receptors are present in abundance on many cancer cells, have been developed. Their cellular uptake, anti-proliferative and apoptosis efficacy were assessed on various cancer cell lines in vitro. Their therapeutic efficacy was evaluated in vivo after tail vein injection to mice bearing B16-F10 melanoma tumors.. The transferrin-bearing lipid-polymer hybrid nanoparticles loaded with plumbagin resulted in the disappearance of 40% of B16-F10 tumors and regression of 10% of the tumors following intravenous administration. They were well tolerated by the mice.. These therapeutic effects, therefore, make transferrin-bearing lipid-polymer hybrid nanoparticles entrapping plumbagin a highly promising anti-cancer nanomedicine.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Liberation; Endocytosis; Female; Humans; Injections, Intravenous; Lipids; Melanoma, Experimental; Mice, Inbred BALB C; Nanoparticles; Naphthoquinones; Polymers; Skin Neoplasms; Thiazoles; Transferrin

Melanoma is a malignant cancer that affects melanocytes and is considered the most aggressive skin-type cancer. The prevalence for melanoma cancer for the last five year is about one million cases. The impact caused of this and other types of cancer, revel the importance of research into potential active compounds. The natural products are an important source of compounds with biological activity and research with natural products may enable the discovery of compounds with potential activity in tumor cells.. The Sulforhodamine B was used to determine cell density after treatment with lawsone derivatives. Apoptosis and necrosis were analyzed by flow cytometer. Morphological changes were observed by fluorescence using the Phalloidin/FITC and DAPI stains. The clonogenic and wound healing assays were used to analyze reduction of colonies formation and migratory capacity of melanoma cells, respectability.. In pharmacological screening, seven compounds derived from lawsone were considered to have high cytotoxic activity (GI > 75%). Three compounds were selected to assess the inhibitory concentration for 50% of cells (IC. The results of this study showed that the evaluated lawsone derivatives have potential activity on tumor cells. The compound 9 is capable of inducing cell death by apoptosis in melanoma cells (B16F10).

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Glycosides; Humans; Melanoma; Mice; Naphthoquinones; Skin Neoplasms; Tumor Stem Cell Assay

Melanoma is a highly drug resistant cancer. To circumvent this problem, a class of synergistically acting drug combinations, which inhibit multiple key pathways in melanoma cells, could be used as one approach for long-term treatment of this deadly disease. A screen has been undertaken on cell lines to identify those that could be combined to synergistically kill melanoma cells. Plumbagin and Celecoxib are two agents that were identified to synergistically kill melanoma cells by inhibiting the COX-2 and STAT3 pathways, which are constitutively activated in up to 70% of melanomas. The combination of these two drugs was more effective at killing melanoma cells than normal cells and decreased cellular proliferation as well as induced apoptosis of cultured cells. The drug combination inhibited development of xenograft melanoma tumors by up to 63% without affecting animal weight or blood biomarkers of organ function, suggesting negligible toxicity. Mechanistically, combination of Celecoxib and Plumbagin decreased melanoma cell proliferation and retarded vascular development of tumors mediated by inhibition of COX-2 and STAT3 leading to decreased levels of key cyclins key on which melanoma cell were dependent for survival.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cyclins; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Humans; Melanoma; Mice, Nude; Naphthoquinones; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

β-lapachone (β-lap), a novel natural quinone derived from the bark of the Pink trumpet tree (Tabebuia avellanedae) has been demonstrated to have anticancer activity. In this study, we investigated whether β-lap exhibits anti-proliferative effects on two human malignant melanoma (HMM) cell lines, G361 and SK-MEL-28. The effects of β-lap on the HMM cell lines were investigated using 3-(4,5-dimethylthiazol-2-yl)‑5-(3-carboxymethoxyphenyl)‑2-(4-sulfophenyl-2H-tetrazolium (MTS) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, Annexin V and Dead cell assay, mitochondrial membrane potential (MMP) assay and western blot analysis. We demonstrated that β-lap significantly induced apoptosis and suppressed cell viability in the HMM cells. Intriguingly, the transcription factor specificity protein 1 (Sp1) was significantly downregulated by β-lap in a dose- and time-dependent manner. Furthermore, β-lap modulated the protein expression level of the Sp1 regulatory genes including cell cycle regulatory proteins and apoptosis-associated proteins. Taken together, our findings indicated that β-lap modulates Sp1 transactivation and induces apoptotic cell death through the regulation of cell cycle- and apoptosis-associated proteins. Thus, β-lap may be used as a promising anticancer drug for cancer prevention and may improve the clinical outcome of patients with cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Down-Regulation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Melanoma; Membrane Potential, Mitochondrial; Naphthoquinones; Neoplasm Proteins; Skin Neoplasms; Sp1 Transcription Factor; Transcriptional Activation

The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Activating Transcription Factor 2; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinogens; Carrier Proteins; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase 4; Epidermis; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Mice; Mice, Inbred DBA; Naphthoquinones; Proto-Oncogene Proteins c-fos; Pyridines; Signal Transduction; Skin Neoplasms; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Transcriptional Activation

Gla-rich protein (GRP) was described in sturgeon as a new vitamin-K-dependent protein (VKDP) with a high density of Gla residues and associated with ectopic calcifications in humans. Although VKDPs function has been related with γ-carboxylation, the Gla status of GRP in humans is still unknown. Here, we investigated the expression of recently identified GRP spliced transcripts, the γ-carboxylation status, and its association with ectopic calcifications, in skin basal cell and breast carcinomas. GRP-F1 was identified as the predominant splice variant expressed in healthy and cancer tissues. Patterns of γ-carboxylated GRP (cGRP)/undercarboxylated GRP (ucGRP) accumulation in healthy and cancer tissues were determined by immunohistochemistry, using newly developed conformation-specific antibodies. Both GRP protein forms were found colocalized in healthy tissues, while ucGRP was the predominant form associated with tumor cells. Both cGRP and ucGRP found at sites of microcalcifications were shown to have in vitro calcium mineral-binding capacity. The decreased levels of cGRP and predominance of ucGRP in tumor cells suggest that GRP may represent a new target for the anticancer potential of vitamin K. Also, the direct interaction of cGRP and ucGRP with BCP crystals provides a possible mechanism explaining GRP association with pathological mineralization.

Topics: alpha-Galactosidase; Breast Neoplasms; Calcinosis; Carcinoma, Basal Cell; Female; Humans; Naphthoquinones; Osteocalcin; Skin Neoplasms; Vitamin K

In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Cutaneous; Administration, Oral; Animals; Antigens, Viral; Antineoplastic Agents, Phytogenic; B-Lymphocytes; Carcinogenesis; Cell Line, Tumor; Female; Herpesvirus 4, Human; Humans; Lawsonia Plant; Male; Naphthoquinones; Papilloma; Plant Extracts; Plant Leaves; Skin Neoplasms; Tetradecanoylphorbol Acetate; Ultraviolet Rays

Plumbagin (PL) (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone, was isolated from the roots of the Plumbago zeylanica L. (also known as Chitrak). The roots of P. zeylanica L. have been used in Indian medicine for >2500 years as an anti-atherogenic, cardiotonic, hepatoprotective and neuroprotective agent. We present here that topical application of non-toxic doses (100-500 nmol) of PL to skin elicits dose-dependent inhibition of ultraviolet radiation (UVR)-induced development of squamous cell carcinomas (SCC). In this experiment, FVB/N mice were exposed to UVR (2 kJ/m(2)) three times weekly from a bank of six Kodacel-filtered FS40 sunlamps (∼ 60% UVB and 40% UVA). Carcinoma incidence in mice treated with vehicle, 100, 200 or 500 nmol PL, at 44 weeks post-UVR, were 86, 80 (P = 0.67), 53 (P = 0.12) and 7% (P = 0.0075), respectively. Both vehicle and PL-treated mice gained weight and did not exhibit any signs of toxicity during the entire period of the experiment. Molecular mechanisms associated with inhibition of UVR-induced development of SCC involved induction of apoptosis and inhibition of cell proliferation. Specific findings are that PL treatment (i) inhibited UVR-induced DNA binding of activating protein-1, nuclear factor-kappaB, Stat3 transcription factors and Stat3-regulated molecules (cdc25A and Survivin); (ii) inhibited protein levels of pERK1/2, PI3K85, pAKTSer473, Bcl(2), BclxL, proliferating cell nuclear antigen and cell cycle inhibitory proteins p27 and p21 and (iii) increased UVR-induced Fas-associated death domain expression, poly (ADP-ribose) polymerase protein cleavage and Bax/Bcl(2) ratio. Taken together, our findings suggest that PL may be a novel agent for the prevention of skin cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Survival; DNA; Female; Mice; Naphthoquinones; Neoplasms, Radiation-Induced; NF-kappa B; Skin Neoplasms; STAT3 Transcription Factor; Transcription Factor AP-1; Ultraviolet Rays

Shikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation.. The mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model.. Among various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells.. Together, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cancer Vaccines; Cell Line, Tumor; Chemokine CCL5; Dendritic Cells; gp100 Melanoma Antigen; Humans; Male; Mice; Naphthoquinones; Skin Neoplasms; Vaccines, DNA

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

Topics: Animals; Apoptosis; B7-2 Antigen; Cancer Vaccines; Cells, Cultured; Dendritic Cells; Female; Genes, MHC Class II; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Naphthoquinones; Skin Neoplasms; Spleen; Th1 Cells; Th17 Cells

Biflorin, an ortho-naphthoquinone, is an active compound found in the roots of Capraria biflora L. It has been reported that biflorin presents anticancer activity, inhibiting both tumor cell line growth in culture and tumor development in mice. The aim of this study was to examine the effectiveness of biflorin treatment using both in-vitro and in-vivo melanoma models. Biflorin displayed considerable cytotoxicity against all tested cell lines, with half maximal inhibitory concentration values ranging from 0.58 μg/ml in NCI H23 (human lung adenocarcinoma) to 14.61 μg/ml in MDA-MB-231 (human breast cancer) cell lines. In a second set of experiments using B16 melanoma cells as a model, biflorin reduced cell viability but did not cause significant increase in the number of nonviable cells. In addition, the DNA synthesis was significantly inhibited. Flow cytometry analysis showed that biflorin may lead to an apoptotic death in melanoma cells, inducing DNA fragmentation and mitochondria depolarization, without affecting membrane integrity. In B16 melanoma-bearing mice, administration of biflorin (25mg/day) for 10 days inhibited tumor growth, and also increased the mean survival rate from 33.3±0.9 days (control) to 44.5±3.4 days (treated). Our findings suggest that biflorin may be considered as a promising lead compound for designing new drugs to be used in the treatment of melanoma.

Topics: Animals; Apoptosis; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Naphthoquinones; Skin Neoplasms

A study of the components of the fruits of Kigelia pinnata was undertaken to identify compounds with potential growth inhibitory activity against human melanoma cells, since extracts from the fruits of this plant have been described in traditional medicine to have application in the treatment of skin cancer and other skin ailments. A bioactivity-guided fractionation process yielded a number of crude fractions, which demonstrated cytotoxicity in vitro against human melanoma cells. Compounds isolated and identified included the isocoumarins, demethylkigelin (1) and kigelin (2), fatty acids, oleic (3) and heneicosanoic acids (4), the furonaphthoquinone, 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-dione (5), and ferulic acid (6). A number of structurally related synthetic compounds were also tested using the MTT assay. The most potent series of these compounds, the furonaphthoquinones, also demonstrated a cytotoxic effect in two human breast cancer cell lines tested.

Topics: Antineoplastic Agents, Phytogenic; Bignoniaceae; Breast Neoplasms; Cell Line, Tumor; Female; Fruit; Growth Inhibitors; Humans; Melanoma; Naphthoquinones; Phytotherapy; Plant Extracts; Skin Neoplasms

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent. However, emergence of drug resistance limits its potential use. Plumbagin is a natural quinonoid compound isolated from plant. In this study, induced apoptosis effect of the combined treatment with plumbagin and TRAIL on human melanoma A375 cell line was examined and possible mechanism was investigated. The cells were divided into four groups: control group, plumbagin group (plumbagin, 5 or 10 mumol/L), TRAIL group (TRAIL, 30 ng/mL) and plumbagin+TRAIL group (combined treatment group). The apoptosis, and the expression of DR4 and DR5 were detected by flow cytometry. The activities of caspase-8 and caspase-3 were determined by colorimetric assay. The results showed that the apoptosis rate was 8.3% in TRAIL group, 10.35%-16.94% in plumbagin group and 52.39%-65.39% in combined treatment group, respectively, with the difference being significant between combined treatment group and plumbagin or TRAIL group (P<0.05 for each). Moreover, plumbagin alone could markedly up-regulate DR5 mRNA and protein expression, and slightly increase DR4 mRNA and protein expression. Treatment of human melanoma A375 cells with plumbagin resulted in the activation of Caspase-3, but not Caspase-8. These results suggest that plumbagin might be useful for TRAIL-based treatment for melanoma.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Caspase 8; Cell Line, Tumor; Humans; Melanoma; Naphthoquinones; Receptors, TNF-Related Apoptosis-Inducing Ligand; Skin Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation

The development of vitiligo has been associated with an improved clinical response in melanoma patients.. We report a case of vitiligo associated with a novel antisurvivin drug and review the literature to determine the pathogenesis of vitiligo occurring during melanoma treatment.. A 78-year-old man with stage IV malignant melanoma developed vitiligo after the first therapeutic cycle of a novel antisurvivin drug. Although his vitiligo remained static, his melanoma continued to progress and he died in 8 months. A review of the literature demonstrates a relationship between vitiligo development and improved clinical response in many melanoma cases treated with immunotherapy; however, the relationship may depend on the type of treatment.. Understanding complex immune responses in vitiliginous skin and melanoma sites is important in order to interpret the development of vitiligo occurring during melanoma treatment.

Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Male; Melanoma; Microtubule-Associated Proteins; Naphthoquinones; Skin Neoplasms; Survivin; Vitiligo

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.

Topics: Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Shape; Comet Assay; Copper; Cytoprotection; Free Radical Scavengers; Humans; Naphthoquinones; Neoplasms; Oxidation-Reduction; Phenanthrolines; Skin Neoplasms

A QSAR study was developed, employing 2D-autocorrelation descriptors and a set of 37 naphthoquinone ester derivatives, in order to model the cytotoxicity of these compounds against oral human epidermoid carcinoma (KB). A comparison with other approaches such as the BCUT, Galvez topological charge indexes, Randić molecular profile, Geometrical, and RDF descriptors was carried out. Mathematical models were obtained by means of the multiple regression analysis (MRA) and the variables were selected using genetic algorithm. Based on the statistical results the 2D-autocorrelation descriptors were considered the best and were able to describe more than 84.2% of the variance in the experimental activity once we controlled for outliers.

Topics: Algorithms; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Esters; Humans; KB Cells; Linear Models; Models, Molecular; Models, Statistical; Naphthoquinones; Quantitative Structure-Activity Relationship; Reproducibility of Results; Skin Neoplasms

Solid tumors are often placed under stress conditions, such as glucose starvation which may result in topoisomerase II drug resistance. In this study, we investigated whether glucose deprivation or substitution by fructose regulates tumor cell apoptosis induced by 2-acetyl furanonaphthoquinone (FNQ). We now show that FNQ exerts much greater antitumor activity than either 7-methoxy 2-ethyl FNQ or 2-ethyl FNQ. Whereas 0.8 microM FNQ induces apoptosis after 16 hours in glucose-supplemented conditions irrespective of bcl-2 overexpression in K1735 melanoma, 0.5 microM FNQ is also effective within 12 hours in low glucose or in fructose-supplemented medium. Under the latter conditions, apoptosis-associated PARP cleavage and cytosolic cytochrome C are increased, together with induction and partial translocation to mitochondria of phosphorylated Jun-N-terminal kinase and massive upregulation of mitochondrial Mn superoxide dismutase. We propose that mitochondrial colocalization of these activities is important in this synergistic anti-tumor effect of FNQ and glucose depletion. Since glucose limitation slows proliferation and decreases efficacy of some genotoxic drugs that trigger apoptosis in rapidly dividing cells, we propose evaluating FNQ as a novel therapeutic anti-cancer adjuvant against slowly proliferating tumors.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Cytochromes c; Furans; Glucose; Glycolysis; Humans; MAP Kinase Kinase 4; Melanoma; Mitochondria; Naphthoquinones; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Superoxide Dismutase; Transcriptional Activation; Tumor Cells, Cultured

Matrix metalloproteinases, like MMP-2 and MMP-9 gelatinases, show multiple functions as extracellular/cell-surface enzymes, and are broadly recognised for their matrix-degrading ability and involvement in cell motility. Given that adherent cells have reduced attachment during migration and also detach from their substratum during apoptosis, we now investigated whether extracellular matrix-bound gelatinases and intracellular MMP-2 and MMP-9 are modified with progression of death-inducing stimuli. This report shows that melanoma cells undergoing death in response to 2-acetyl furanonaphtoquinone (FNQ) as evidenced by greater Annexin V binding, increased cytosolic expression of pro-MMP-2 and intracellular activation of particulate MMP-9. These changes were associated with early activation of a substrate-attached 40 kDa gelatinase reciprocal with changes in extracellular matrix-bound activated MMP-2. A subsequent activation of secreted MMP-9 and induction of apoptosis-associated fragmentation of poly ADP-Ribose polymerase (PARP) correlated with cell detachment. Our data suggests that intracellularly activated gelatinases may cleave survival-associated substrates other than gelatin that share the Gly-Leu/Iso-Pro like collagen-binding acetylcholinesterase, thereby linking them to apoptosis associated with cell detachment.

Topics: Animals; Annexin A5; Apoptosis; Cell Line, Tumor; Cell Membrane; Enzyme Activation; Extracellular Matrix; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma; Mice; Naphthoquinones; Neoplasm Invasiveness; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Up-Regulation; Water

As a part of screening studies for cancer chemopreventive agents (anti-tumor promoters), six natural and four synthetic naphthoquinones and five of their analogs were tested for their inhibitory activities against Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. Some of the 1,4-naphthoquinones and their analogs were found to show remarkably potent activities, without showing any cytotoxicity. 1,4-Furanonaphthoquinone (5) and its analog (9) isolated from Avicennia plants (Avicenniaceae), having an alcoholic OH group on the dihydrofuran-ring, displayed the most potent activity. Furthermore, avicenol-A (9) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The result of the present investigation indicated that some of these 1,4-naphthoquinones and their analogs might be valuable as potent cancer chemopreventive agents.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antigens, Viral; Carcinogens; Female; Humans; In Vitro Techniques; Mice; Mice, Inbred ICR; Naphthoquinones; Papilloma; Plant Extracts; Plants, Medicinal; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Virus Activation

In continuation of our studies of natural and synthetic products as cancer chemopreventive agents, we have examined a number of naphthoquinone derivatives including monomeric, dimeric and tetrameric naphthaquinones occurring in the Diospyros and other selected plant genera. Several synthetic naphthoquinones were also evaluated. Initially these compounds were tested for in vitro anti-tumor promoting effect on Epstein-Barr virus early antigen activation produced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and thereafter in in vivo on two-stage mouse skin carcinogenesis. Our studies show some of these compounds have potent anti-tumor promoting activity.

Topics: Animals; Antigens, Viral; Carcinogens; Cells, Cultured; Female; Mice; Mice, Inbred ICR; Naphthoquinones; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate

Topics: Angiokeratoma; Antifibrinolytic Agents; Fabry Disease; Heparin Antagonists; Humans; Naphthoquinones; Retinoids; Skin Neoplasms; Vitamin K; Vitamin K 3