Estefanía Burgos‐Morón

Universidad de Sevilla

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José Manuel Calderón‐Montaño

Universidad de Sevilla

Miguel López‐Lázaro

Universidad de Sevilla

Manuel Luís Orta

Universidad de Sevilla

Julio José Jiménez‐Alonso

Universidad de Sevilla

Emilio Guillén-Mancina

Universidad de Sevilla

Santiago Mateos

Universidad de Sevilla

Nuria Pastor

Universidad de Sevilla

Thomas Helleday

Science for Life Laboratory

Víctor Jiménez-González

Universidad de Sevilla

Andreas Höglund

Ericsson (Sweden)

Cooperative Institutions

Universidad de Sevilla

Science for Life Laboratory

Karolinska Institutet

Uppsala University

Svenska Örtmedicinska Institute

Centre National de la Recherche Scientifique

Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana

Hospital Universitario Doctor Peset

Universitat de València

Instituto de Biomedicina de Sevilla

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Aziridines from alkenyl-β-D-galactopyranoside derivatives: Stereoselective synthesis and in vitro selective anticancer activity

European Journal of Medicinal Chemistry (2013)

José M. Vega‐Pérez Carlos Palo‐Nieto Margarita Vega‐Holm Purificación Góngora-Vargas José Manuel Calderón‐Montaño

10.1016/j.ejmech.2013.10.020

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Citations (14)

The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions

Nucleic Acids Research (2014)

Manuel Luís Orta Andreas Höglund José Manuel Calderón‐Montaño Inmaculada Domı́nguez Estefanía Burgos‐Morón

Decitabine (5-aza-2′-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) recognizes 5-azadC-induced lesions in DNA and mediates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci after 5-azadC treatment, suggesting a novel and specific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defective cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relocation to DNA damage sites, disrupts XRCC1–DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5-azadC to improve treatment of MDS and AML.

XRCC1

Olaparib

10.1093/nar/gku638

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Citations (81)

The in vivo antitumor activity of cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact

Oncogene (2013)

José Manuel Calderón‐Montaño Estefanía Burgos‐Morón Miguel López‐Lázaro

Artifact (error)

Cardiac glycoside

10.1038/onc.2013.229

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Citations (43)

Artificial Diets with Selective Restriction of Amino Acids and Very Low Levels of Lipids Induce Anticancer Activity in Mice with Metastatic Triple-Negative Breast Cancer

Emilio Guillén-Mancina Julio José Jiménez‐Alonso José Manuel Calderón‐Montaño Víctor Jiménez-González Patricia Díaz-Ortega

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were used as positive controls. AA manipulation led to modest improvements in mice survival when the levels or lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Mice fed the artificial diets as monotherapy lived longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Triple-negative breast cancer

10.20944/preprints202212.0399.v1

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Citations (3)

Discovery of the first potent and selective inhibitors of the human dCTP pyrophosphatase 1 (dCTPase)

Sabin Llona‐Minguez Andreas Höglund Sylvain A. Jacques Lars Johansson José Manuel Calderón‐Montaño

Pyrophosphatases

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A Diet Lacking Selenium, but Not Zinc, Copper or Manganese, Induces Anticancer Activity in Mice with Metastatic Cancers

Nutrients (2024)

Patricia Díaz-Ortega José Manuel Calderón‐Montaño Julio José Jiménez‐Alonso Emilio Guillén-Mancina Víctor Jiménez-González

Selenium, zinc, copper, and manganese are essential components of antioxidant enzymes involved in the elimination of reactive oxygen species (ROS). Given that cancer cells produce high levels of ROS and the accumulation of ROS can lead to cell death, cancer cells may be susceptible to strategies that reduce ROS elimination. In this work, we prepared several artificial diets that contained normal carbohydrate, protein, and lipid levels but lacked selenium, zinc, copper, or manganese. The anticancer activity of these diets was examined in a metastatic ovarian cancer model, established by injecting ID8

10.3390/nu16142249

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Guanidine-reactive agent phenylglyoxal induces DNA damage and cancer cell death

Pharmacological Reports (2012)

José Manuel Calderón‐Montaño Estefanía Burgos‐Morón Manuel Luís Orta Nuria Pastor Concepción Pérez‐Guerrero

Phenylglyoxal

Comet Assay

Topoisomerase inhibitor

10.1016/s1734-1140(12)70949-0

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Citations (10)

Role of the Intracellular pH in the Metabolic Switch between Oxidative Phosphorylation and Aerobic Glycolysis - Relevance to Cancer

José Manuel Calderón‐Montaño Estefanía Burgos‐Morón Concepción Pérez‐Guerrero Javier Salvador Antonio Robles

Cellular energy in the form of ATP can be produced through oxidative phosphorylation and through glycolysis. Since oxidative phosphorylation requires oxygen and generates ATP more efficiently than glycolysis, it has been assumed for many years that the presence or absence of oxygen determines that cel ls generate energy through ox idat ive phosphorylation or through glycolysis. Although cells must activate glycolysis in the absence of oxygen to produce ATP, it is now accepted that they can activate both glycolysis and oxidative phosphorylation in the presence of oxygen. In fact, normal proliferating cells and tumor cells are known to have a high glycolytic activity in the presence of adequate oxygen levels, a phenomenon known as aerobic glycolysis or the Warburg effect. Recent observations have demonstrated that the activation of aerobic glycolysis plays a major role in carcinogenesis and tumor growth. Understanding the mechanisms involved in the metabolic switch between oxidative phosphorylation and aerobic glycolysis may therefore be important for the development of potential preventive and therapeutic interventions. In this article, we discuss the role of the intracellular pH in the metabolic switch between oxidative phosphorylation and aerobic glycolysis. We propose that, in the presence of adequate oxygen levels, the intracellular pH may play a key role in determining the way cells obtain energy, an alkaline pH driving aerobic glycolysis and an acidic pH driving oxidative phosphorylation.

Anaerobic glycolysis

Warburg Effect

Metabolic pathway

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Citations (24)

Selective Cytotoxic Activity of New Lipophilic Hydroxytyrosol Alkyl Ether Derivatives

Journal of Agricultural and Food Chemistry (2013)

José Manuel Calderón‐Montaño Andrés Madrona Estefanía Burgos‐Morón Manuel Luís Orta Santiago Mateos

Recent data suggest that hydroxytyrosol, a phenolic compound of virgin olive oils, has anticancer activity. This communication reports the synthesis of decyl and hexadecyl hydroxytyrosyl ethers, as well as the cytotoxic activity of hydroxytyrosol and a series of seven hydroxytyrosol alkyl ether derivatives against A549 lung cancer cells and MRC5 non-malignant lung fibroblasts. Hydroxytyrosyl dodecyl ether (HTDE) showed the highest selective cytotoxicity, and possible mechanisms of action were investigated; results suggest that HTDE can moderately inhibit glycolysis, induce oxidative stress, and cause DNA damage in A549 cells. The combination of HTDE with the anticancer drug 5-fluorouracil induced a synergistic cytotoxicity in A549 cancer cells but not in non-malignant MRC5 cells. HTDE also displayed selective cytotoxicity against MCF7 breast cancer cells versus MCF10 normal breast epithelial cells in the 1–30 μM range. These results suggest that the cytotoxicity of HTDE is more potent and selective than that of parent compound hydroxytyrosol.

Hydroxytyrosol

10.1021/jf400796p

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Citations (44)

Abstract 1260: Polymerase kappa determines the sensitivity of MTH1 inhibitors to cisplatin-resistant cell

Cancer Research (2016)

Kumar Sanjiv Helge Gad Sean G. Rudd Rachel M. Hurley Patric Herr

Abstract Resistance is one the main reason for overall decrease in survival of cancer patient treated with cisplatin in different types of cancer. Cisplatin kills cancer cells by various mechanisms, but mainly through formation of inter- and intra stand crosslinks of DNA. Different types of translesion polymerase including Polymerase kappa (POLK) are involved in repair of DNA lesions. We observed high expression levels of POLK in cisplatin resistant bladder and ovarian cancer cells compared to parental cells. Due to its low proof-reading activity POLK can incorporate 8-oxo-dGTP into DNA. The MTH1 protein (Nudix hydrolase- NUDT1) sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Recently we have generated MTH1 inhibitors that damage the DNA and induce cancer specific cell death through incorporation of more oxidized dNTPs. We found cisplatin resistant bladder cancer cells (NTUB1/P) were more sensitive to MTH1 inhibitors in comparison to parental NTUB1 cells. As POLK is involved in incorporation of 8-oxo-dGTP into DNA, we hypothesized that high expression levels of POLK in cisplatin resistant cells make them more sensitive to MTH1 inhibitors as more 8-oxo-dGTP would be incorporated into DNA, resulting in more DNA damage and cell death in comparison to parental cells. Indeed, we observes higher induction of cleaved-PARP, γH2AX, cleaved-Caspase 3 and more annexin v positive cells in cisplatin resistant NTUB1/P cells in comparison to parental NTUB1 cells upon treatment with MTH1 inhibitors. MTH1 inhibitor also significantly delays the NTUB1/P xenograft tumor growth in comparison to vehicle treatment in immunosuppressive mice. Knocking down POLK in cisplatin resistant NTUB1/P cells by siRNA resulted in decreased incorporation of 8-oxo-dGTP and sensitivity to MTH1 inhibitors compared to non target control cells. Overexpression of POLK in NTUB1 and NTUB1/P cells results in further sensitization to MTH1 inhibitors. In conclusion elevated levels of POLK in cisplatin resistance cells determines increased sensitivity towards MTH1 inhibitors. Thus MTH1 inhibitors can be a potential promising therapy for the treatment of cisplatin resistant tumors in patients. Citation Format: Kumar Sanjiv, Helge Gad, Sean Rudd, Rachel Hurley, Patric Herr, José Manuel Calderón Montaño, Oliver Mortusewicz, Tobias Koolmeister, Sylvain Jaques, Estefanía Burgos Morón, Andreas Hoglund, Te-Chang Lee, Martin Scobie, Scott Kaufmann, John Weroha, Ulrika Warpman Berglund, Andrea Wahner Hendrickson, Thomas Helleday. Polymerase kappa determines the sensitivity of MTH1 inhibitors to cisplatin-resistant cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1260.

POLK

10.1158/1538-7445.am2016-1260

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