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Food Interactions, Sirtuins, Genes, Homeostasis, and General Discussion
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
In tumorigenesis (cancer development), Sirt1 seems to play a contradictory role, acting as both a tumor promoter and tumor suppressor (70, 73, 87, 95–98). Sirt1 was the first sirtuin family member to be discovered and is still the most studied. Its biological role in cancer has been studied extensively, yet there are conflicting results regarding the association between the two, as Sirt1 is known to suppress or promote cancer depending on its cellular content or type (97). It is similar to survivin, a protein of the inhibitor of apoptosis family. As tumor suppressor, sirtuin1 inhibits oncogenes and oncoproteins. Sirt1 knockdown accelerated tumor xenograft formation by HCT116 cells, whereas Sirt1 overexpression inhibited tumor formation (70). High Sirt1 levels were also detected in normal colon mucosa and benign adenomas; and Sirt1 overexpression was observed in about 25% of stage I/II/III colorectal adenocarcinomas but rarely found in advanced stage IV tumors (70). On the other hand, up-regulated Sirt1 has been described in cancer cell lines as well as in tissue samples from patients with human lung cancer, prostate cancer, colon carcinoma, and chronic lymphocytic leukemia cells (70). These results raise the possibility that inhibition of Sirt1 might suppress cancer cell proliferation. However, reduced Sirt1 levels have been also reported in breast cancer and hepatic cell carcinoma compared with their normal controls, while slight increase or no change of Sirt1 levels were detected in other tumors (70).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the oncology area, EZN3042, a Survivin inhibitor jointly developed by Enzon Pharmaceuticals Inc and Santaris Pharma a/s progressed into the clinic for patients with solid tumors and lymphomas but did not progress past Phase 1. In the diagnostics area, LNA nucleotides have been used as probes for FISH, real-time Allele-specific PCR, SNP genotyping, fluorescence polarization, and double-dye oligo techniques. They have also been used as mRNA antisense to increase the sensitivity and specificity of expression in DNA microarrays.
Antileukemic Treatment Targeted at Apoptosis Regulators
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Simone Fulda, Klaus-Michael Debatin
One promising therapeutic strategy directed at apoptosis regulators is the neutralization of IAPs. IAPs are a family of endogenous caspase inhibitors and comprise eight human analogs, which are XIAP, cIAP1, cIAP2, survivin, livin or melanoma-IAP (ML-IAP), apollon, NAIP, and ILP-2 (26). Among the IAP family members, XIAP is best known for its antiapoptotic function (65). XIAP blocks apoptosis by binding to active caspase-3 and -7 and also by interfering with caspase-9 activation (26). In addition, XIAP inhibits apoptosis via mechanisms unrelated to its ability to inhibit caspases. For example, XIAP can activate the NF-κB pathway by forming a complex with the TAK1 kinase and its cofactor TAB1 (66–69). Mechanistically, the XIAP-mediated NF-κB activation can be dissociated from its caspase-inhibitory effects and requires the E3 ubiquitin ligase activity of XIAP (66–69). The role of survivin in the regulation of apoptosis and proliferation is more complex compared with other IAP family proteins (70). Besides its role as a regulator of apoptosis, survivin is also involved in the control of mitosis (70).
Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohammed S. Taghour, Hazem Elkady, Wagdy M. Eldehna, Nehal M. El-Deeb, Ahmed M. Kenawy, Eslam B. Elkaeed, Aisha A. Alsfouk, Mohamed S. Alesawy, Ahmed M. Metwaly, Ibrahim. H. Eissa
Overexpression of the Bcl2 gene can inhibit the apoptotic cell death and partially the nonapoptotic cell death, which has a role in arrest of cell cycle. Meanwhile, overexpression of Bcl-xL enhances autophagic cell death60. Moreover, Survivin is a pro-survival protein that is overexpressed in many cancer cells in the G2-M phase. This protein has been linked to tumour progression control and resistance to cancer chemotherapeutics. Furthermore, the transforming growth factor (TGF) is one of various proteins that secreted by transformed cells and stimulate the growth of non-cancerous cells in addition to its role as initiators of the signalling pathway that suppresses the early development of cancer cells61. Dysregulation of TGF-β activation and signalling may result in apoptosis.
Apoptosis targeted therapies in acute myeloid leukemia: an update
Published in Expert Review of Hematology, 2020
Somedeb Ball, Gautam Borthakur
Birinapant, a bivalent IAP inhibitor, is effective in causing cell death through activation of the apoptosis when used in conjunction with HMA [81]. In a phase I study evaluating single-agent birinapant therapy in patients with relapsed/refractory AML, the best response at the time of reporting was stable disease in some patients; exacerbation of autoimmune diseases and Bell’s palsy were notable adverse events [82]. Combination of birinapant with AZA showed an acceptable safety profile and evidence of clinical activity in a phase Ib study in patients with MDS [83]. Although AEG35156 (XIAP inhibitor antisense oligonucleotide) showed promising results in preclinical and early phase clinical studies, its incorporation in the reinduction chemotherapy did not improve the remission rate in a randomized phase II trial in patients with primary refractory AML [84,85]. LY2181308, another antisense oligonucleotide targeting the survivin expression, was well tolerated in early phase clinical studies. It showed a clinically relevant response when used as a single agent and in combination with chemotherapy in relapsed/refractory AML [86]. ASTX 660, a dual inhibitor of XIAP and cIAP, is in clinical trial in combination with ASTX727 (oral hypomethylating agent) in relapsed, refractory AML (NCT04155580).
Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies
Published in Cancer Investigation, 2019
Chin Liang Lee, Sanggeetha Veeramani, Aidin Molouki, Swee Hua Erin Lim, Warren Thomas, Suet Lin Chia, Khatijah Yusoff
Survivin is an apoptosis inhibitory protein that is over-expressed in many tumour cells. Inhibition of cancer cell growth can be achieved through direct survivin antagonism, or by using survivin RNA interference. A recombinant adenovirus expressing survivin siRNA (D55-Sur-EGFP) down-regulated the expression of survivin protein in CRC cells [26]. There was a significant cytopathic effect even at low multiplicity of infection (MOI) by the virus [27]. In vivo mouse studies found a reduction in tumour volume with ZD55-Sur-EGFP treatment [27], that was enhanced in combination with 5-FU co-treatment [26]. Thus again there is an augmentation of standard chemotherapy drugs when tumour cells are simultaneously infected with recombinant adenoviruses that suppress cell survival pathways.