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- Banerji, Shantanu, et al.
(författare)
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Important differences between topoisomerase-I and -II targeting agents
- 2006
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Ingår i: Cancer Biology & Therapy. - : Landes Bioscience. - 1538-4047 .- 1555-8576. ; 5:8, s. 965-966
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Commentary to: Activation of ATM and Histone H2AX Phosphorylation Induced by Mitoxantrone But Not by Topotecan is Prevented by the Antioxidant N-acetyl-L-Cysteine Xuan Huang, Akira Kurose, Toshiki Tanaka, Frank Traganos, Wei Dai and Zbigniew Darzynkiewicz
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| 4. |
- Deland, Lily, et al.
(författare)
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Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib
- 2021
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Ingår i: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 22:3, s. 184-195
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32–33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10–16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient’s condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.
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| 5. |
- El-Awady, Raafat A, et al.
(författare)
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Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy
- 2015
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Ingår i: Cancer Biology & Therapy. - Philadelphia, PA, United States : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 16:7, s. 1056-1070
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 – 4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.
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| 7. |
- Gu, Xiaolian, 1976-, et al.
(författare)
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TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN
- 2007
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Ingår i: Cancer Biology & Therapy. - 1538-4047 .- 1555-8576. ; 6:12, s. 1979-1983
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Tidskriftsartikel (refereegranskat)abstract
- p63, a member of the p53 family, is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and some other tumors of epithelial origin. As a transcription factor, p63 can bind to p53-type response elements and there is some overlap between p53 family transcriptional targets. Tumor necrosis factor receptor associated factor 4 (TRAF4) is a p53 regulated gene which is overexpressed in many human carcinomas. We investigated the involvement of p63 in regulation of TRAF4 and the expression of the TRAF4 protein in SCCHN. Disrupting endogenous p63 expression resulted in downregulation of TRAF4 mRNA and protein in an SCCHN cell line. Endogenous p63 bound to the TRAF4 promoter in vivo and reporter assays showed that p63, p73 and p53 can all transactivate TRAF4, with TAp63 isoforms being the most potent activators. The level of TRAF4 activation by TAp63 was two-fold higher than by p53, and TRAF4 was ten-fold more responsive to TAp63 than another p63-target, IGFBP3. Nuclear expression of TRAF4 was seen in normal oral epithelium and highly/moderately differentiated SCCHN, whereas cytoplasmic expression of TRAF4 was seen in poorly differentiated SCCHN. These results indicate that TRAF4 is a common target of p53 family members and that localization of TRAF4 is associated with differentiation of SCCHN cells.
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| 9. |
- Itani, Wafica, et al.
(författare)
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Anti colon cancer components from lebanese sage (Salvia libanotica) essential oil : Mechanistic basis
- 2008
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Ingår i: Cancer Biology & Therapy. - : Informa UK Limited. - 1538-4047 .- 1555-8576. ; 7:11, s. 1765-1773
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Tidskriftsartikel (refereegranskat)abstract
- Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)), and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 h); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53(+/+) cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.
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| 10. |
- Jain, Samatha M., et al.
(författare)
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Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy : A review
- 2024
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Ingår i: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 25:1
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Forskningsöversikt (refereegranskat)abstract
- Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as - the PI3K/AKT pathway, Wnt/β-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.
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