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Jakub Golab

Publications and source records attributed to Jakub Golab.

At least 19 recordsLinked to original sources
PubMed2007

Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy.

Photodynamic therapy (PDT) is an established anticancer modality utilizing the photogeneration of reactive oxygen species (ROS) to kill the cancer cells and hypericin is a promising photosensitizer for the treatment of bladder tumors. In this paper we characterize the signaling pathways and the mechanisms leading to the up-regulation of the antioxidant enzyme heme oxygenase (HO-1) in PDT treated cancer cells. We show that PDT engages the p38(MAPK) and PI3K signaling cascades for HO-1 induction. p38(MAPK) inhibitors or small interfering RNA (siRNA) for p38(MAPK) suppress HO-1 induction after PDT and complete repression is attained when p38 and PI3K antagonists are combined. Blocking these signaling pathways increases additively the propensity of the cells to undergo PDT-induced apoptosis, mirroring the effect of HO-1 silencing. Conversely, increasing HO-1 protein level by hemin prior to irradiation is cytoprotective. HO-1 stimulation by PDT is dependent on transcription and de novo protein synthesis and it is preceded by the nuclear accumulation of the Nrf2 transcription factor, which is reduced by inhibitors of p38(MAPK) and PI3K. Altogether these results indicate that stimulation of HO-1 expression by hypericin-PDT is a cytoprotective mechanism governed by the p38(MAPK) and PI3K pathways, likely through the control of the nuclear availability of the Nrf2 pool.

Anthracenes↗
PubMed2006

Berberine, a natural cholesterol reducing product, exerts antitumor cytostatic/cytotoxic effects independently from the mevalonate pathway.

The aim of this study was to investigate the role of the mevalonate pathway in the cytostatic/cytotoxic effects of berberine, a natural plant alkaloid that reduces cholesterol concentration. Berberine as well as lovastatin, an inhibitor of the mevalonate pathway, exerted dose-dependent cytostatic/cytotoxic effects against human breast cancer cells (MDA-MB231). Although the mevalonate pathway metabolites (mevalonic acid, farnesyl pyrophosphate, geranylgeranyl pyrophosphate) effectively reversed cytostatic/cytotoxic effects of lovastatin against MDA-MB231 cells, they were not effective in influencing the cytostatic/cytotoxic effects of berberine. The cytostatic/cytotoxic effects of berberine do not seem to result from inhibition of the mevalonate pathway.

Anticholesteremic Agents↗
PubMed2005

Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells in in vitro and in vivo studies.

Advanced melanoma is a highly malignant tumor with an increasing incidence that has a poor prognosis due to resistance to common therapeutic strategies. We have demonstrated previously that cyclosporine A (CsA) induces apoptosis of rat glioma cells, reactive astrocytes, and fibroblasts. In our present study, we investigated effects of CsA and its nonimmunosuppressive derivative NIM811 on survival of human and murine melanoma cells. We demonstrated that CsA and NIM811 affect survival of human and murine melanoma cells and induce morphological changes, alterations in nuclear morphology and an internucleosomal DNA fragmentation, consistent with an apoptotic type of death. Western blot analysis showed an activation of caspases 9, 7, 3 and PARP cleavage detectable at 24 hr after exposure of human melanoma cells to the drugs. CsA and NIM811 induced a significant increase in subG1 population of murine B16F10 melanoma cells indicative of apoptotic DNA fragmentation. Studies in murine model of melanoma showed that NIM811, but not CsA, retards tumor progression and significantly decreases tumor volume after intratumoral application. Our findings indicate that CsA and its derivatives may be new candidates for the treatment of melanoma patients.

Animals↗
PubMed2005

Technology evaluation: SB-485232, GlaxoSmithKline.

GlaxoSmithKline (formerly SmithKline Beecham), under license from Hayashibara, is developing SB-485232, a recombinant human interleukin-18 cancer immunotherapy for the potential treatment of immunologically sensitive cancers, including melanoma and renal cell cancer. The compound is currently undergoing phase II clinical trials.

Adjuvants, Immunologic↗
PubMed2004

CpG immunostimulatory oligodeoxynucleotide 1826 enhances antitumor effect of interleukin 12 gene-modified tumor vaccine in a melanoma model in mice.

PURPOSE: The effectiveness of interleukin (IL)-12-secreting tumor vaccines in the treatment of mouse tumors could be enhanced by concurrent application of cytokines and costimulatory molecules. We investigated the therapeutic potential of IL-12 gene-transduced melanoma vaccine in combination with CpG immunostimulatory oligodeoxynucleotide (ODN) 1826, an adjuvant known to favor development of Th1-biased immune response, in a B78-H1 (B78) melanoma model in mice. EXPERIMENTAL DESIGN: Mice injected with B78 melanoma cells were treated with irradiated IL-12 gene-transduced B78 cells [B78/IL-12(X)] and/or ODN 1826. Mechanisms responsible for the antitumor effects of the treatment were investigated using fluorescence-activated cell sorter analysis, a standard (51)Cr releasing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and ELISA. RESULTS: Single injection of B78/IL-12(X) cells had no effect on tumor growth, whereas seven consecutive daily injections of ODN 1826 markedly inhibited tumor progression with occasional curative effects. When used in combination, B78/IL-12(X) cells and ODN 1826 caused additional tumor growth reduction and eradication of tumors in 62% of treated mice. The combined treatment activated local inflammatory response against tumor but also induced systemic antitumor immunity. In vitro studies have shown that when used together, B78/IL-12(X) cells and ODN 1826 induced a potent Th1 response and suggested the role of IFN-gamma in activation of the host immune response. The antitumor effects in double-treated mice were accompanied by the development of cytotoxic effectors in the spleen and activation of macrophages. CONCLUSIONS: The results provided the evidence that the combination of IL-12 gene-modified melanoma vaccine and ODN 1826 induces synergistically systemic and local antitumor immunity.

Animals↗
PubMed2004

Role of the ubiquitin-proteasome pathway in the diagnosis of human diseases.

The ubiquitin-proteasome pathway constitutes the major system for nuclear and extralysosomal cytosolic protein degradation in eukaryotic cells. A plethora of cell proteins implicated in the maintenance and regulation of essential cellular processes undergoes processing and functional modification by proteolytic degradation via the ubiquitin-proteasome pathway. Deregulations of the pathway have been shown to contribute to the pathogenesis of several human diseases, such as cancer, neurodegenerative, autoimmune, genetic and metabolic disorders, most of them exhibiting abnormal accumulation and altered composition of components of the pathway that is suitable for diagnostic proceedings. While the ubiquitin-proteasome pathway is currently exploited to develop novel therapeutic strategies, it is less regarded as a diagnostic area. Future research should lead to an improved understanding of the pathophysiology of the ubiquitin-proteasome pathway with the aim of allowing the development of subtle diagnostic strategies.

Autoimmune Diseases↗
PubMed2004

Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin.

Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase are commonly used in the clinic to treat hypercholesterolemia and have been reported to exert antitumor effects. Cerivastatin is a novel, synthetic and the most pharmacologically potent inhibitor of HMG-CoA reductase. We decided to examine the cytostatic/cytotoxic activity of cerivastatin against human breast cancer cell lines and to test whether the effects of cerivastatin could be potentiated by doxorubicin and cisplatin. Cytostatic/cytotoxic effects of cerivastatin used alone or in the combination with chemotherapeutics were measured with MTT assay. The cell cycle distribution and apoptosis induction were evaluated with flow cytometer. The expression of p21 and p27 cyclin-dependent kinase inhibitors was measured with Western blotting. Isobologram analysis was performed to study the drug interactions. We observed that cerivastatin exerts cytostatic/cytotoxic effects against four human tumor cell lines (T-47D, T4-2, MDA-MB-231, MCF-7). We also demonstrated that cerivastatin exerts growth inhibitory effect through induction of p21 cyclin-dependent kinase inhibitor and inhibition of cell cycle progression. In the two tumor cell lines studied, one sensitive (MDA-MB-231) and one moderately resistant (T4-2) to the cytostatic/cytotoxic effects of cerivastatin we examined the effects of combined treatment with cerivastatin and either doxorubicin or cisplatin. Cerivastatin potentiated cytostatic/cytotoxic effects of cisplatin against T4-2 cells and those of doxorubicin against both cell lines. In T4-2 cells the interaction between doxorubicin and cerivastatin and between cisplatin and cerivastatin was found to be synergistic. Altogether, these studies indicate that cerivastatin is another HMG-CoA reductase inhibitor with potent antitumor effects.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Differential influence of pentoxifylline on murine colon adenocarcinoma- and melanoma-derived metastatic tumor development in lungs.

Pentoxifylline (PTX), a methylxanthine derivative, is commonly and in most cases chronically used in patients suffering from peripheral vascular diseases. It increases erythrocyte flexibility, reduces blood viscosity and improves microcirculatory flow. Moreover, PTX has been found to enhance anticancer activity of some chemotherapeutic agents and ionizing irradiation. On the other hand, PTX has been recently shown to inhibit anticancer response and promote murine tumor growth in liver. In this study we show that PTX facilitates development of murine colon adenocarcinoma- but not melanoma-derived tumors also in lungs. It could suggest that tumor-promoting PTX activity is tissue-independent, although, it might depend on the cancer cell line.

Adenocarcinoma↗
PubMed2004

Potentiated antitumor effects of a combination therapy with a farnesyltransferase inhibitor L-744,832 and butyrate in vitro.

Farnesyltransferase inhibitors, butyrate and butyric acid derivatives have previously been reported to exert anti-tumor activity in experimental models in vitro and in vivo and have recently gained acceptance as potential anticancer agents. In our study, we examined antitumor effects of a combination of a farnesyltransferase inhibitor L-744,832 and butyrate in vitro against MDA-MB-231 and MIA PaCa-2 human cancer cells. This combination therapy showed synergistic antitumor activity against MDA-MB-231 cells, which was at least in part due to induction of p27KIP1 expression. Both drugs increased intracellular levels of p53 as well but there was no significant difference between the groups treated with single drugs and the group treated with their combination. In MIA PaCa-2 cells, the combination therapy exerted additive antitumor activity. Our results illustrate possible application of the farnesyltransferase inhibitor L-744,832 and butyrate as a combination therapy of cancer.

Alkyl and Aryl Transferases↗
PubMed2004

Demethylating agent 5-aza-2'-deoxycytidine enhances expression of TNFRI and promotes TNF-mediated apoptosis in vitro and in vivo.

Promoter hypermethylation within CpG islands plays an important role in the silencing of numerous genes involved in tumor growth including tumor suppressor genes and genes encoding proteins involved in the execution of apoptosis. Here we show that CpG islands are also found within the promoter regions of both human and mouse TNFR1 (TNFRSF1) genes. Selective inhibition of methyltransferases with 5-aza-2'-deoxycytidine increases the expression of TNFR1 in human (WM35) and murine (B16F10) melanoma cells and sensitizes them to TNF-induced apoptosis both in vitro and in vivo. Treatment of mice with the combination of 5-aza-2'-deoxycytidine and recombinant TNF leads to potentiated antitumor effects. Importantly the antitumor efficacy of the combination treatment is shown when both drugs are used in doses that do not exert any antitumor effects when used alone. Altogether our studies show that the combination treatment with 5-aza-2'-deoxycytidine and TNF might be effective in the treatment of melanoma.

Animals↗
PubMed2004

Lovastatin potentiates antitumor effects of saquinavir against human lymphoma cells.

Antiretroviral protease inhibitors have been shown to cause hyperlipidemia, raising concerns for the possibility of cardiovascular complications among HIV-infected patients. Statins have been successfully used in the management of hypercholesterolemia and were shown to exert antitumor effects. We report here that lovastatin and saquinavir exert cytostatic/cytotoxic effects against Daudi and Raji human lymphoma cells. Importantly, lovastatin potentiates the antitumor effects of saquinavir against these lymphomas in an additive manner. Addition of statins to antiretroviral treatment might therefore decrease some of its side effects while potentiating the antitumor effectiveness.

Cell Line, Tumor↗
PubMed2003

Potential antitumor effects of statins (Review).

Statins, which have been introduced to the clinic for the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid (MA). MA is the precursor in the biosynthesis of isoprenoid compounds including cholesterol, dolichol and ubiquinone. Furthermore, mevalonate-derived prenyl groups enable precise cellular localization and function of many proteins such as Ras and Rho proteins. Therefore, besides lowering cholesterol level, statins exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival but also participate in the regulation of cell shape and motility. Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process. In preclinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics. The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity. The results of several clinical studies of statins in cancer patients including phase I, phase I/II, and phase II trials have been published. Although evaluation of the therapeutic efficacy is not the purpose of early clinical trials and all conclusions might be premature at this stage, some preliminary conclusions have already been drawn. The results of these studies do not show any significant therapeutic effects of statins in cancer patients. However, the results of one of these studies suggest that statins could effectively strengthen the therapeutic activity of some chemotherapeutics. This observation seems to agree with the results of preclinical studies. However, as toxic side effects of statins have been particularly evident in their combination with some other drugs great caution should be advised while planning clinical trials based on combination therapy including statins in cancer patients.

Animals↗
PubMed2002

Antitumor effects of photodynamic therapy are potentiated by 2-methoxyestradiol. A superoxide dismutase inhibitor.

Photodynamic therapy (PDT), a promising therapeutic modality for the management of solid tumors, is a two-phase treatment consisting of a photosensitizer and visible light. Increasing evidence indicates that tumor cells in regions exposed to sublethal doses of PDT can respond by rescue responses that lead to insufficient cell death. We decided to examine the role of superoxide dismutases (SODs) in the effectiveness of PDT and to investigate whether 2-methoxyestradiol (2-MeOE(2)), an inhibitor of SODs, is capable of potentiating the antitumor effects of this treatment regimen. In the initial experiment we observed that PDT induced the expression of MnSOD but not Cu,Zn-SOD in cancer cells. Pretreatment of cancer cells with a cell-permeable SOD mimetic, Mn(II)-tetrakis(4-benzoic acid)porphyrin chloride, and transient transfection with the MnSOD gene resulted in a decreased effectiveness of PDT. Inhibition of SOD activity in tumor cells by preincubation with 2-MeOE(2) produced synergistic antitumor effects when combined with PDT in 3 murine and 5 human tumor cell lines. The combination treatment was also effective in vivo producing retardation of the tumor growth and prolongation of the survival of tumor-bearing mice. We conclude that inhibition of MnSOD activity by 2-MeOE(2) is an effective treatment modality capable of potentiating the antitumor effectiveness of PDT.

2-Methoxyestradiol↗
PubMed2002

Augmented antitumour effects of combination therapy with TNP-470 and chemoimmunotherapy in mice.

PURPOSE: To investigate antitumour efficacy of the combination of the antiangiogenic agent TNP-470 combined with chemoimmunotherapy in different tumour models in mice MATERIALS: B6D2F1 mice and BALB/c mice were inoculated in the footpad of the right hind limb with B16F10 melanoma cells or colon adenocarcinoma cells C-26, respectively. Subsequently, they received therapy consisting of TNP-470 and/or IL-12 and tumour growth was observed. In the melanoma model this therapy regimen was combined with cisplatin in a subtherapeutic dose. The antiangiogenic action of the tested agents was evaluated using tumour-induced angiogenesis assay in vivo. In order to analyse interactions between TNP-470 (or cisplatin) and IFN-gamma on tumour cells in vitro, the following methods were used: MTT assay, Western blot analysis, and flow cytometry analysis. RESULTS: Administration of the combined therapy with TNP-470 and IL-12 resulted in augmented antitumour activity in colon-26 and B16F10 melanoma models. Addition of cisplatin further enhanced efficacy of this combined therapy in the melanoma model. We showed that antitumour activity of this combined therapy is mediated by multiple mechanisms: not only is enhancement of the antiangiogenic activity mediated by TNP-470 and IL-12 but also by the synergistic cytostatic/cytotoxic action of IL-12-induced IFN-gamma and TNP-470 or cisplatin on tumour cells. The experiments revealed that TNP-470 together with IFN-gamma leads to the increased expression of p21 protein in cancer cells, which in turn may contribute to their cytostatic/cytotoxic action in vitro. CONCLUSION: Our experiments show a successful TNP-470-based combination therapy and suggest that the enhancement of the antitumour activity could be explained by a concomitant effect on both endothelial and tumour cell compartments.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Potentiated antitumor effects of butyrate and actinomycin D in melanoma model in mice.

Butyrate and butyric acid derivatives are well known to induce differentiation and apoptosis of tumor cells and have also recently gained acceptance as potential anticancer agents. In this study we observed an increased expression of mTNFalpha in tumor tissues in mice treated with butyrate prodrug tributyrin. Since in in vitro experiments we observed a potentiating effects of TNFalpha and actinomycin D on B16F10 cells and also a synergistic interaction was previously claimed between those agents, we investigated the anti-tumor activity of the combination therapy with butyrate and actinomycin D in the B16F10 melanoma model in mice. The combination of the drugs resulted in a strongly potentiated tumor growth retardation in melanoma bearing mice. However the B16F10 cells in vitro did not produce any detectable amounts of TNFalpha. The presented data strongly suggest that one of the mechanism of this successful drug combination could depend on the interaction of the actinomycin D with butyrate-induced TNFalpha produced by stromal or tumor infiltrating immune cells. The results illustrate also the possible application of this combination in cancer therapy.

Animals↗
PubMedDate not supplied

IL-12 or IL-15, unlike IL-2, does not interact with histamine in augmenting cytotoxicity of splenocytes against melanoma cells and YAC-1 cells.

It has been suggested that histamine by its ability to downregulate the production of macrophage-derived reactive oxygen species might effectively potentiate the cytotoxic activity of cytokine-stimulated NK cells. Histamine thus reverses negative regulation of NK cells treated with IL-2 and IFN-alpha in the presence of macrophages. We confirm that histamine potently enhances cytotoxic activity of IL-2-stimulated NK cell-enriched splenocytes admixed with macrophages against B16F10 melanoma cells and YAC-1 cells. This stimulation results in production of high amounts of INF-gamma and TNF-alpha. Interestingly, IL-15 by itself promotes production of reactive oxygen species. Although histamine decreased reactive oxygen species production from the cultures of IL-15-stimulated NK cell-enriched splenocytes admixed with macrophages, it did not potentiate the cytotoxicity of IL-15. Further, we demonstrate that histamine-mediated potentiation of cytotoxicity is not applicable to IL-12, another potent activator of NK cell activity.

Animals↗
PubMedDate not supplied

A single injection of immature dendritic cells is able to induce antitumour response against a murine colon adenocarcinoma with a low apoptotic index.

Dendritic cells can induce an immune response as competent antigen presenting cells. It has been reported that immature bone marrow derived dendritic cells are capable of inducing an immune response against tumours displaying significant apoptosis. It is still controversial, however whether immature dendritic cells can also induce an immune response against tumours with a low apoptotic index. C-26 adenocarcinoma cells were injected into the footpad of Balb/c mice. One million immature dendritic cells cultured in vitro using GM-CSF and IL-4 were injected into the tumour-bearing footpad on day 6 after tumour cell inoculation. Tumour volume was measured starting from day 5 after tumour cell inoculation. Mice were observed daily for survival. The growing tumours were characterized by a low apoptotic index. There was a statistically significant delay in the tumour growth and a significant prolongation of the survival time in DC treated group as compared with controls (p<0.05). Immature dendritic cells injected into the site of tumour growth are able to induce a potent antitumour response which leads to the retardation of the tumour growth and the prolongation of the life survival time. Here we show that even a single injection of immature dendritic cells is able to induce a significant immune response against tumours with low apoptotic index.

Adenocarcinoma↗