Ändra sökning
Länk till posten
Permanent länk

Direktlänk
Helleday, Thomas
Publikationer (10 of 121) Visa alla publikationer
Al-Ubaidi, F. L. T., Schultz, N., Egevad, L., Granfors, T. & Helleday, T. (2012). CASTRATION THERAPY OF PROSTATE CANCER RESULTS IN DOWNREGULATION OF HIF-1 alpha LEVELS. International Journal of Radiation Oncology, Biology, Physics, 82(3), 1243-1248
Öppna denna publikation i ny flik eller fönster >>CASTRATION THERAPY OF PROSTATE CANCER RESULTS IN DOWNREGULATION OF HIF-1 alpha LEVELS
Visa övriga...
2012 (Engelska)Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 82, nr 3, s. 1243-1248Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background and Purpose: Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer. Methods and Materials: In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in cancer was determined by immunofluorescence. Results: Among biopsy specimens taken before castration, strong HIF-1 alpha expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10-30) in 3 patients, and background levels of HIF-1 alpha (mean intensity 0-10) in 6 patients. Downregulation of HIF-1 alpha expression after castration was observed in all 5 patients with strong HIF-1 alpha precastration expression. HIF-1 alpha expression was also reduced in 2 of 3 patients with weak HIF-1 alpha precastration expression. Conclusions: Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.

Nyckelord
Hypoxia-inducible factor, HIF-1 alpha, Prostate cancer
Nationell ämneskategori
Urologi och njurmedicin
Identifikatorer
urn:nbn:se:su:diva-76984 (URN)10.1016/j.ijrobp.2011.10.038 (DOI)000300423500064 ()
Anmärkning

5

Tillgänglig från: 2012-06-05 Skapad: 2012-05-28 Senast uppdaterad: 2024-02-09Bibliografiskt granskad
Abdallah, Q. M. A., Phillips, R. M., Johansson, F., Helleday, T., Cosentino, L., Abdel-Rahman, H., . . . Pors, K. (2012). Minor structural modifications to alchemix influence mechanism of action and pharmacological activity. Biochemical Pharmacology, 83(11), 1514-1522
Öppna denna publikation i ny flik eller fönster >>Minor structural modifications to alchemix influence mechanism of action and pharmacological activity
Visa övriga...
2012 (Engelska)Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 83, nr 11, s. 1514-1522Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

Nyckelord
Anthraquinone, H2AX phosphorylation, MDR, Topoisomerase II, NER, p53
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:su:diva-79770 (URN)10.1016/j.bcp.2012.02.017 (DOI)000303078700005 ()
Anmärkning

AuthorCount:13;

Tillgänglig från: 2012-09-12 Skapad: 2012-09-11 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Chatzakos, V., Slätis, K., Djureinovic, T., Helleday, T. & Hunt, M. C. (2012). N-Acyl Taurines are Anti-Proliferative in Prostate Cancer Cells. Lipids, 47(4), 355-361
Öppna denna publikation i ny flik eller fönster >>N-Acyl Taurines are Anti-Proliferative in Prostate Cancer Cells
Visa övriga...
2012 (Engelska)Ingår i: Lipids, ISSN 0024-4201, E-ISSN 1558-9307, Vol. 47, nr 4, s. 355-361Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Endocannabinoids have been implicated in cancer development and cause heterogenous effects in tumor cells, by inducing apoptosis, reducing migration, causing anti-angiogenic activity and alterations in the cell cycle resulting in growth arrest. Recently, several novel amides of fatty acids that are structurally related to endocannabinoids have been isolated from mammalian sources, although the functions of these fatty amides are not well studied. One group of these novel fatty acid amides are the N-acyl taurines (fatty acids conjugated to the amino acid taurine). This study examined if N-acyl taurines, specifically N-arachidonoyl taurine and N-oleoyl taurine could function in a similar way to endocannabinoids and result in cell cycle alterations or growth arrest in the human prostate adenocarcinoma cell line PC-3. PC-3 cells were treated with various concentrations of N-arachidonoyl taurine and N-oleoyl taurine and cell proliferation and viability was measured using resazurin and colony formation assays. Effects of N-acyl taurines on the cell cycle was measured using FACS analysis. Treatment with N-arachidonoyl taurine and N-oleoyl taurine resulted in a significant reduction in proliferation of PC-3 cells, even at concentrations as low as 1 mu M. Treatment with N-oleoyl taurine resulted in an increased number of cells in the subG1 population, suggesting apoptosis, and a lower number of cells in S-phase of the cell cycle. In summary, our results show that novel biologically active lipids, the N-acyl taurines, result in reduced proliferation in PC-3 cells.

Nyckelord
N-Arachidonoyl taurine, N-Oleoyl taurine, Fatty acid amide hydrolase, N-Acyl amino acids, PC-3 cells, Cell proliferation
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
molekylärgenetik
Identifikatorer
urn:nbn:se:su:diva-76070 (URN)10.1007/s11745-011-3639-9 (DOI)000302095400002 ()
Anmärkning

5

Tillgänglig från: 2012-05-08 Skapad: 2012-05-08 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Wilsker, D., Chung, J. H., Pradilla, I., Petermann, E., Helleday, T. & Bunz, F. (2012). Targeted Mutations in the ATR Pathway Define Agent-Specific Requirements for Cancer Cell Growth and Survival. Molecular Cancer Therapeutics, 11(1), 98-107
Öppna denna publikation i ny flik eller fönster >>Targeted Mutations in the ATR Pathway Define Agent-Specific Requirements for Cancer Cell Growth and Survival
Visa övriga...
2012 (Engelska)Ingår i: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 11, nr 1, s. 98-107Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.

Nationell ämneskategori
Genetik Mikrobiologi
Identifikatorer
urn:nbn:se:su:diva-76757 (URN)10.1158/1535-7163.MCT-11-0675 (DOI)000299308200010 ()
Anmärkning
6Tillgänglig från: 2012-05-17 Skapad: 2012-05-16 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Urbin, S. S., Elvers, I., Hinz, J. M., Helleday, T. & Thompson, L. H. (2012). Uncoupling of RAD51 focus formation and cell survival after replication fork stalling in RAD51D null CHO cells. Environmental and Molecular Mutagenesis, 53(2), 114-124
Öppna denna publikation i ny flik eller fönster >>Uncoupling of RAD51 focus formation and cell survival after replication fork stalling in RAD51D null CHO cells
Visa övriga...
2012 (Engelska)Ingår i: Environmental and Molecular Mutagenesis, ISSN 0893-6692, E-ISSN 1098-2280, Vol. 53, nr 2, s. 114-124Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In vertebrate cells, the five RAD51 paralogs (XRCC2/3 and RAD51B/C/D) enhance the efficiency of homologous recombination repair (HRR). Stalling and breakage of DNA replication forks is a common event, especially in the large genomes of higher eukaryotes. When cells are exposed to agents that arrest DNA replication, such as hydroxyurea or aphidicolin, fork breakage can lead to chromosomal aberrations and cell killing. We assessed the contribution of the HRR protein RAD51D in resistance to killing by replication-associated DSBs. In response to hydroxyurea, the isogenic rad51d null CHO mutant fails to show any indication of HRR initiation, as assessed by induction RAD51 foci, as expected. Surprisingly, these cells have normal resistance to killing by replication inhibition from either hydroxyurea or aphidicolin, but show the expected sensitivity to camptothecin, which also generates replication-dependent DSBs. In contrast, we confirm that the V79 xrcc2 mutant does show increased sensitivity to hydroxyurea under some conditions, which was correlated to its attenuated RAD51 focus response. In response to the PARP1 inhibitor KU58684, rad51d cells, like other HRR mutants, show exquisite sensitivity (>1000-fold), which is also associated with defective RAD51 focus formation. Thus, rad51d cells are broadly deficient in RAD51 focus formation in response to various agents, but this defect is not invariably associated with increased sensitivity. Our results indicate that RAD51 paralogs do not contribute equally to cellular resistance of inhibitors of DNAreplication, and that the RAD51 foci associated with replication inhibition may not be a reliable indicator of cellular resistance to such agents.

Nyckelord
homologous recombination, RAD51 paralogs, RAD51 foci, hydroxyurea, DNA replication
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:su:diva-76985 (URN)10.1002/em.21672 (DOI)000299831600004 ()
Anmärkning

5

Tillgänglig från: 2012-06-05 Skapad: 2012-05-28 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Segal-Raz, H., Mass, G., Baranes-Bachar, K., Lerenthal, Y., Wang, S.-Y., Chung, Y. M., . . . Shiloh, Y. (2011). ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair. EMBO Reports, 12(7), 713-719
Öppna denna publikation i ny flik eller fönster >>ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair
Visa övriga...
2011 (Engelska)Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 12, nr 7, s. 713-719Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia-telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5'-OH and dephosphorylates 3'-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKP-Ser 114 and Ser 126-are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.

Nyckelord
ATM, DNA damage response, double strand break repair, polynucleotide kinase/phosphatase, protein phosphorylation
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:su:diva-67006 (URN)10.1038/embor.2011.96 (DOI)000292325700023 ()
Anmärkning
authorCount :12Tillgänglig från: 2011-12-28 Skapad: 2011-12-22 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Ström, C. E., Mortusewicz, O., Finch, D., Parsons, J. L., Lagerqvist, A., Johansson, F., . . . Helleday, T. (2011). CK2 phosphorylation of XRCC1 facilitates dissociation from DNA and single-strand break formation during base excision repair. DNA Repair, 10(9), 961-969
Öppna denna publikation i ny flik eller fönster >>CK2 phosphorylation of XRCC1 facilitates dissociation from DNA and single-strand break formation during base excision repair
Visa övriga...
2011 (Engelska)Ingår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, nr 9, s. 961-969Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

CK2 phosphorylates the scaffold protein XRCC1, which is required for efficient DNA single-strand break (SSB) repair. Here, we express an XRCC1 protein (XRCC1(ckm)) that cannot be phosphorylated by CK2 in XRCC1 mutated EM9 cells and show that the role of this post-translational modification gives distinct phenotypes in SSB repair and base excision repair (BER). Interestingly, we find that fewer SSBs are formed during BER after treatment with the allcylating agent dimethyl sulfate (DMS) in EM9 cells expressing XRCC1(ckm) (CKM cells) or following inhibition with the CK2 inhibitor 2-dimethylamino-4,5,6,7tetrabromo-1H-benzimidazole (DMAT). We also show that XRCC1(ckm) protein has a higher affinity for DNA than wild type XRCC1 protein and resides in an immobile fraction on DNA, in particular after damage. We propose a model whereby the increased affinity for DNA sequesters XRCC1(ckm) and the repair enzymes associated with it, at the repair site, which retards kinetics of BER. In conclusion, our results indicate that phosphorylation of XRCC1 by CK2 facilitates the BER incision step, likely by promoting.

Nyckelord
CK2, XRCC1, Dimethyl sulfate, Mammalian cells, Base excision repair, Single-strand break, Chinese hamster ovary cells
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:su:diva-67294 (URN)10.1016/j.dnarep.2011.07.004 (DOI)000295242600007 ()
Anmärkning
authorCount :10Tillgänglig från: 2011-12-27 Skapad: 2011-12-27 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Bauerschmidt, C., Woodcock, M., Stevens, D. L., Hill, M. A., Rothkamm, K. & Helleday, T. (2011). Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells. Experimental Cell Research, 317(3), 330-337
Öppna denna publikation i ny flik eller fönster >>Cohesin phosphorylation and mobility of SMC1 at ionizing radiation-induced DNA double-strand breaks in human cells
Visa övriga...
2011 (Engelska)Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 317, nr 3, s. 330-337Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cohesin, a hetero-tetrameric complex of SMC1, SMC3, Rad21 and Scc3, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. Following DNA damage, cohesin accumulates at and promotes the repair of DNA double-strand breaks. In addition, phosphorylation of the SMC1/3 subunits contributes to DNA damage-induced cell cycle checkpoint regulation. The aim of this study was to determine the regulation and consequences of SMC1/3 phosphorylation as part of the cohesin complex. We show here that the ATM-dependent phosphorylation of SMC1 and SMC3 is mediated by H2AX, 53BP1 and MDC1. Depletion of RAD21 abolishes these phosphorylations, indicating that only the fully assembled complex is phosphorylated. Comparison of wild type SMC1 and SMC1S966A in fluorescence recovery after photo-bleaching experiments shows that phosphorylation of SMC1 is required for an increased mobility after DNA damage in G2-phase cells, suggesting that ATM-dependent phosphorylation facilitates mobilization of the cohesin complex after DNA damage.

Nyckelord
ATM, SMC1, SMC3, Cohesin, Ionizing radiation, DNA repair
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:su:diva-67353 (URN)10.1016/j.yexcr.2010.10.021 (DOI)000286367700007 ()
Anmärkning

authorCount :6

Tillgänglig från: 2011-12-28 Skapad: 2011-12-28 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Svensson, L. M., Jemth, A.-S., Desroses, M., Loseva, O., Helleday, T., Högbom, M. & Stenmark, P. (2011). Crystal structure of human MTH1 and the 8-oxo-dGMP product complex. FEBS Letters, 585(16), 2617-2621
Öppna denna publikation i ny flik eller fönster >>Crystal structure of human MTH1 and the 8-oxo-dGMP product complex
Visa övriga...
2011 (Engelska)Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, nr 16, s. 2617-2621Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9 angstrom) and its complex with the product 8-oxo-dGMP (1.8 angstrom). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.

Nyckelord
MTH1, MutT, Oxidative damage, 8-oxo-dGTPase, NUDT1, 8-oxo-dGTP, Tautomer
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-68308 (URN)10.1016/j.febslet.2011.07.017 (DOI)000293826300012 ()
Forskningsfinansiär
VetenskapsrådetStiftelsen för strategisk forskning (SSF)Wenner-Gren StiftelsernaCancerfonden
Anmärkning

authorCount :7

Tillgänglig från: 2012-01-13 Skapad: 2012-01-03 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Kondo, N., Takahashi, A., Mori, E., Noda, T., Zdzienicka, M. Z., Thompson, L. H., . . . Ohnishi, T. (2011). FANCD1/BRCA2 Plays Predominant Role in the Repair of DNA Damage Induced by ACNU or TMZ. PLOS ONE, 6(5), e19659
Öppna denna publikation i ny flik eller fönster >>FANCD1/BRCA2 Plays Predominant Role in the Repair of DNA Damage Induced by ACNU or TMZ
Visa övriga...
2011 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 6, nr 5, s. e19659-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Nimustine (ACNU) and temozolomide (TMZ) are DNA alkylating agents which are commonly used in chemotherapy for glioblastomas. ACNU is a DNA cross-linking agent and TMZ is a methylating agent. The therapeutic efficacy of these agents is limited by the development of resistance. In this work, the role of the Fanconi anemia (FA) repair pathway for DNA damage induced by ACNU or TMZ was examined. Cultured mouse embryonic fibroblasts were used: FANCA(-/-), FANCC(-/-), FANCA(-/-)C(-/-), FANCD2(-/-) cells and their parental cells, and Chinese hamster ovary and lung fibroblast cells were used: FANCD1/BRCA2mt, FANCG(-/-) and their parental cells. Cell survival was examined after a 3 h ACNU or TMZ treatment by using colony formation assays. All FA repair pathways were involved in ACNU-induced DNA damage. However, FANCG and FANCD1/BRCA2 played notably important roles in the repair of TMZ-induced DNA damage. The most effective molecular target correlating with cellular sensitivity to both ACNU and TMZ was FANCD1/BRCA2. In addition, it was found that FANCD1/BRCA2 small interference RNA efficiently enhanced cellular sensitivity toward ACNU and TMZ in human glioblastoma A172 cells. These findings suggest that the down-regulation of FANCD1/BRCA2 might be an effective strategy to increase cellular chemo-sensitization towards ACNU and TMZ.

Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:su:diva-68139 (URN)10.1371/journal.pone.0019659 (DOI)000290386800030 ()
Anmärkning
authorCount :13Tillgänglig från: 2012-01-03 Skapad: 2012-01-03 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Organisationer

Sök vidare i DiVA

Visa alla publikationer