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  1. Article ; Online: Implementing Curcumin in Translational Oncology Research

    Koraljka Gall Trošelj / Ivana Samaržija / Marko Tomljanović / Renata Novak Kujundžić / Nikola Đaković / Anamarija Mojzeš

    Molecules, Vol 25, Iss 5240, p

    2020  Volume 5240

    Abstract: Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are ... ...

    Abstract Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.
    Keywords cancer therapy ; clinical trials ; microbiota ; IL-17 ; nicotinamide N -methyltransferase ; metabolic reprogramming ; Organic chemistry ; QD241-441
    Subject code 610
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer

    Renata Novak Kujundžić / Marin Prpić / Nikola Đaković / Nina Dabelić / Marko Tomljanović / Anamarija Mojzeš / Ana Fröbe / Koraljka Gall Trošelj

    International Journal of Molecular Sciences, Vol 22, Iss 5681, p

    2021  Volume 5681

    Abstract: The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD + ) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either ...

    Abstract The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD + ) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H 2 O 2 . Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD + -consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD + homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD + flux by stalling liberation of NAM and reducing NAD + synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD + depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
    Keywords nicotinamide N-methyltransferase ; nicotinamide adenine dinucleotide ; aldehyde oxidase ; cancer ; epigenetic reprogramming ; senescence ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 333
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response

    Koraljka Gall Trošelj / Marko Tomljanović / Morana Jaganjac / Tanja Matijević Glavan / Ana Čipak Gašparović / Lidija Milković / Suzana Borović Šunjić / Brigitta Buttari / Elisabetta Profumo / Sarmistha Saha / Luciano Saso / Neven Žarković

    Molecules, Vol 27, Iss 1468, p

    2022  Volume 1468

    Abstract: Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the ... ...

    Abstract Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of Antioxidant Response Element (ARE)-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.
    Keywords 4-hydroxynonenal ; therapy resistance ; cancer stem cells ; tumor associated macrophages (TAMs) ; tumor associated neutrophils (TANs) ; polarization ; Organic chemistry ; QD241-441
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

    Anamarija Mojzeš / Marko Tomljanović / Lidija Milković / Renata Novak Kujundžić / Ana Čipak Gašparović / Koraljka Gall Trošelj

    International Journal of Molecular Sciences, Vol 21, Iss 5, p

    2020  Volume 1661

    Abstract: In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate ... ...

    Abstract In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.
    Keywords pkm1 ; pkm2 ; shmt2 ; phgdh ; stat3 ; serine ; intracellular localization ; ethanol ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Curcumin and its Potential for Systemic Targeting of Inflamm-Aging and Metabolic Reprogramming in Cancer

    Renata Novak Kujundžić / Višnja Stepanić / Lidija Milković / Ana Čipak Gašparović / Marko Tomljanović / Koraljka Gall Trošelj

    International Journal of Molecular Sciences, Vol 20, Iss 5, p

    2019  Volume 1180

    Abstract: Pleiotropic effects of curcumin have been the subject of intensive research. The interest in this molecule for preventive medicine may further increase because of its potential to modulate inflamm-aging. Although direct data related to its effect on ... ...

    Abstract Pleiotropic effects of curcumin have been the subject of intensive research. The interest in this molecule for preventive medicine may further increase because of its potential to modulate inflamm-aging. Although direct data related to its effect on inflamm-aging does not exist, there is a strong possibility that its well-known anti-inflammatory properties may be relevant to this phenomenon. Curcumin’s binding to various proteins, which was shown to be dependent on cellular oxidative status, is yet another feature for exploration in depth. Finally, the binding of curcumin to various metabolic enzymes is crucial to curcumin’s interference with powerful metabolic machinery, and can also be crucial for metabolic reprogramming of cancer cells. This review offers a synthesis and functional links that may better explain older data, some observational, in light of the most recent findings on curcumin. Our focus is on its modes of action that have the potential to alleviate specific morbidities of the 21st century.
    Keywords curcumin ; oxidative metabolites ; inflamm-aging ; cancer ; metabolic reprogramming ; direct protein binding ; IL-17 ; STAT3 ; SHMT2 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 570
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Nutritional Stress in Head and Neck Cancer Originating Cell Lines

    Lidija Milković / Marko Tomljanović / Ana Čipak Gašparović / Renata Novak Kujundžić / Dina Šimunić / Paško Konjevoda / Anamarija Mojzeš / Nikola Đaković / Neven Žarković / Koraljka Gall Trošelj

    Cells, Vol 8, Iss 9, p

    The Sensitivity of the NRF2-NQO1 Axis

    2019  Volume 1001

    Abstract: Nutritional stress disturbs the cellular redox-status, which is characterized by the increased generation of reactive oxygen species (ROS). The NRF2-NQO1 axis represents a protective mechanism against ROS. Its strength is cell type-specific. FaDu, Cal 27 ...

    Abstract Nutritional stress disturbs the cellular redox-status, which is characterized by the increased generation of reactive oxygen species (ROS). The NRF2-NQO1 axis represents a protective mechanism against ROS. Its strength is cell type-specific. FaDu, Cal 27 and Detroit 562 cells differ with respect to basal NQO1 activity. These cells were grown for 48 hours in nutritional conditions (NC): (a) Low glucose−NC2, (b) no glucose, no glutamine−NC3, (c) no glucose with glutamine−NC4. After determining the viability, proliferation and ROS generation, NC2 and NC3 were chosen for further exploration. These conditions were also applied to IMR-90 fibroblasts. The transcripts/transcript variants of NRF 2 and NQO 1 were quantified and transcript variants were characterized. The proteins (NRF2, NQO1 and TP53) were analyzed by a western blot in both cellular fractions. Under NC2, the NRF2-NQO1 axis did not appear activated in the cancer cell lines. Under NC3, the NRF2-NQO1axis appeared slightly activated in Detroit 562. There are opposite trends with respect to TP53 nuclear signal when comparing Cal 27 and Detroit 562 to FaDu, under NC2 and NC3. The strong activation of the NRF2-NQO1 axis in IMR-90 resulted in an increased expression of catalytically deficient NQO1, due to NQO1*2/*2 polymorphism (rs1800566). The presented results call for a comprehensive exploration of the stress response in complex biological systems.
    Keywords glucose deprivation ; glutamine deprivation ; viability ; proliferation ; ROS ; NRF2-NQO1 axis ; IMR-90 ; NQO1 transcript variants ; rs1800566 ; TP53 mutation ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Expression of sirtuin 1 and 2 is associated with poor prognosis in non-small cell lung cancer patients.

    Ivana Grbesa / María J Pajares / Elena Martínez-Terroba / Jackeline Agorreta / Ana-Matea Mikecin / Marta Larráyoz / Miguel A Idoate / Koraljka Gall-Troselj / Ruben Pio / Luis M Montuenga

    PLoS ONE, Vol 10, Iss 4, p e

    2015  Volume 0124670

    Abstract: BACKGROUND:Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology. MATERIAL AND ... ...

    Abstract BACKGROUND:Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology. MATERIAL AND METHODS:Protein levels of SIRT1 and SIRT2 were determined in non-small cell lung cancer (NSCLC) cell lines and primary tumors from 105 patients. Changes in proliferation were assessed after SIRT1 and SIRT2 downregulation in lung cancer cell lines using siRNA-mediated technology or tenovin-1, a SIRT1 and SIRT2 inhibitor. RESULTS:High SIRT1 and SIRT2 protein levels were found in NSCLC cell lines compared with non-tumor lung epithelial cells. The expression of SIRT1 and SIRT2 proteins was also significantly higher in lung primary tumors than in normal tissue (P<0.001 for both sirtuins). Stronger nuclear SIRT1 staining was observed in adenocarcinomas than in squamous cell carcinomas (P=0.033). Interestingly, in NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively). Moreover, the combination of high SIRT1 and SIRT2 expression was an independent prognostic factor for shorter recurrence-free survival (P=0.002) and overall survival (P=0.022). In vitro studies showed that SIRT1 and/or SIRT2 downregulation significantly decreased proliferation of NSCLC. CONCLUSIONS:Our results support the hypothesis that SIRT1 and SIRT2 have a protumorigenic role in lung cancer, promoting cell proliferation. Moreover, the expression of these proteins is associated with poor prognosis in NSCLC patients and may help to identify those NSCLC patients with high risk of recurrence that could benefit from adjuvant therapy after resection.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 616
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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