Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3K

Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.

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“…DNA-PK inhibitors NU7441and KU0060648 can be used to inhibit Akt activation [169–171]. These inhibitors have been studied as anti-cancer agents.…”

Section: Akt Inhibitorsmentioning

confidence: 99%

The critical role of Akt in cardiovascular function

Abeyrathna

2015

Vascular Pharmacology

335

222

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“…Furthermore, 14 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. A counter-screen against other members of the PI3K PIKK family revealed that some of the compounds were potent mixed DNA-PK and PI3K inhibitors, including 14 [30,31]. The favourable biological activity of 14 was complemented by superior drug-like properties compared to NU7441 (13), and acceptable plasma protein binding, combined with weak activity against hERG and a panel of cytochrome P450 (CYP) drug-metabolising enzymes (Table 4) [30].…”

Section: (Scheme 4)mentioning

confidence: 99%

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

Harnor¹,

Brennan²,

Cano³

2017

Med chem

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The catalytic activity of DNA-dependent protein kinase (DNA-PK) is central to its ability to repair lethal DNAdouble strand breaks (DSBs). This includes repair of DSB lesions following therapeutic treatment of cancer cells or resulting from oxidative stress or oncogene-induced transcription. As a tactic to induce tumour chemo-and radio-sensitisation, numerous attempts have been made to identify small molecule inhibitors of DNA-PK activity. This review examines the structures of known reversible and irreversible inhibitors, including those based upon chromen-4-one, arylmorpholine, and benzaldehyde scaffolds. VX-984 and M3814 are recent examples of DNA-PK catalytic inhibitors that have progressed into clinical development, the results from which should help to further advance our understanding of whether this approach represents a promising therapeutic strategy for the treatment of cancer.

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“…PI3K ve DNA-PK'nin ikili inhibitörü olan KU-0060648 etoposit ve doksorubisin birlikte kullanıldığında DNA-PKc olan hücrelerde sitotoksiteyi arttırırken, DNA-PKc olmayanlarda etkili olmamıştır. Bu bulgu DNA-PK inhibisyonunun sitotoksisitede önemli olduğunu göstermiştir [24]. görevi olduğunu da göstermektedir [31].…”

Section: Discussionunclassified

The Effects of Topoisomerase Inhibition on Dna Repair and Apoptosis in L929 Fibroblasts

Dogan¹,

Yar²,

Ergin³

et al. 2013

Turk J Bioch

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Objective: DNA repair pathways in cells are essential for the maintenance of genome integrity, and for countering the induction of tumorigenesis. Topoisomerase II is a nuclear enzyme that functions during both DNA replication and transcription. The topoisomerase II inhibitor etoposide is an antineoplastic drug that has been used to generate DNA damage and maintain apoptosis. Etoposide blocks cell division by interfering with the topoisomerase II and generates double strand breaks. Application of topoisomerase II inhibitors leads to the formation of double strand breaks that are rapidly repaired following removal of the drug.In the present study, we searched the apoptotic events and early double strand DNA repair process that prevent the apoptotic cell death of L929 fibroblasts in response to treatment with etoposide. Methods: Cytotoxicty of etoposide on L929 cells was determined in a time and dose dependent manner with MTT assay. The double strand DNA breaks were determined with comet assay. Acridin orange/Ethidium bromide fluorescence staining and Caspase 3/7 activity assays were performed in determined etoposide concentrations at 24 hour. Quantitative mRNA expressions of DNA repair genes (Ku70, Ku80, BRCA2, Rad51, XRCC4) were determined after etoposide treatment. Results:The levels of apoptotic cell markers and DNA double strand breaks were elevated in the increasing doses and time. The relative expression levels of Rad51, XRCC4 and BRCA2 were unstable in a time and dose dependent manner. Ku80 levels were generally decreased in etoposide treated groups when compared with controls. However, Ku70 was highly expressed at 9 and 12 hour with the increasing doses. Conclusion: According to the results of this study, etoposide activates apoptotic events. Also, low expression levels of DNA repair enzymes prevent cell survival from DNA damage.

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Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3K

Cited by 117 publications

References 37 publications

The critical role of Akt in cardiovascular function

The critical role of Akt in cardiovascular function

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

The Effects of Topoisomerase Inhibition on Dna Repair and Apoptosis in L929 Fibroblasts

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