Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity

Spasokoukotskaja, Tatjana; Sasvári-Székely, Mária; Keszler, Gergely; Albertioni, Freidoun; Eriksson, Staffan; Staub, Maria

doi:10.1016/s0959-8049(99)00223-3

Cited by 59 publications

(23 citation statements)

References 22 publications

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“…The present study also showed that ZD6474, gemcitabine, and ionizing radiation increased the expression of dCK. This result agrees with previous studies, which indicated that stress stimuli and nucleoside analogues had a stimulatory effect on dCK (37). Because of the profound influence of dCK on tumor resistance to gemcitabine (38), the enhanced expression of dCK after ZD6474 exposure may explain the synergistic interaction observed in the ZD6474!gemcitabine combination.…”

Section: Discussionsupporting

confidence: 92%

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

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Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.Pancreatic cancer is a highly malignant illness that has steadily increased in incidence over recent decades, and it is now the fourth leading cause of death from cancer in the Western world. Despite this, there has been little improvement in prognosis over the past 20 years (1). Due to the delay of clinical symptoms, pancreatic cancer is usually detected at an advanced stage, and survival ranges between 4 and 6 months after diagnosis. Moreover, because of its aggressive biological behavior, this malignancy has a grim prognosis even following surgical resection, and the 5-year survival for all stages of the disease remains below 4% (2). Therefore, pancreatic cancer represents a clinical challenge and novel therapeutic approaches are warranted.Several studies showed that pancreatic cancer is characterized by dysregulation of molecular mechanisms involved in cell proliferation, invasiveness, and angiogenesis (3). Epidermal growth factor receptor (EGFR) is a key driver of cell proliferation, and

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Section: Discussionsupporting

confidence: 92%

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Bianco¹,

Giovannetti

Ciardiello³

et al. 2006

Clinical Cancer Research

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“…The first mechanism reported to control dCK activity was retro-inhibition by dCTP, although its physiological relevance is questionable [4][5][6]. Thereafter, several studies [7][8][9][10] suggested that dCK activity could be regulated by posttranslational modification, which was definitively confirmed by our group. We established that dCK is a phosphoprotein containing at least four phosphorylation sites: Thr-3, Ser-11, Ser-15 and Ser-74, the latter being the major phosphorylated residue and the only one to play a role in the regulation of dCK activity [11].…”

Section: Introductionsupporting

confidence: 62%

Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser‐74 dephosphorylation

et al. 2014

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Edited by Zhijie Chang Keywords:Deoxycytidine kinase Nucleoside analog Ser-74 phosphorylation Protein phosphatase Ser/Thr protein phosphatase 2A a b s t r a c t Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation at concentrations reported to specifically target PP2A. In line with this, purified PP2A, but not PP1, dephosphorylated recombinant pSer-74-dCK. In cell lysates, the Ser-74-dCK phosphatase activity was found to be latent, Mn 2+ -activated, responsive to PP2A inhibitors, and diminished after PP2A-immunodepletion. Use of siRNAs allowed concluding definitively that PP2A constitutively dephosphorylates dCK in cells and negatively regulates its activity.

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“…Indeed, as an inhibitor of de novo purine biosynthesis, pemetrexed may enhance the expression of enzymes involved in salvage nucleoside pathway, including dCK, as a compensatory mechanism. This result is in agreement with previous studies that indicated that several inhibitors of DNA biosynthesis, such as cladribine and fludarabine, had a stimulatory effect on dCK (38). These findings may have implications for rational design of drug regimens incorporating gemcitabine and other agents modulating the activity of the key enzyme dCK (Fig.…”

Section: Molecular Determinants Related To Drug Sensitivitysupporting

confidence: 93%

Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer

Giovannetti

Mey

Nannizzi

et al. 2006

Molecular Cancer Therapeutics

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Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16 INK4 . Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment.

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Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity

Cited by 59 publications

References 22 publications

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer

Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser‐74 dephosphorylation

Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer

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