Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of mouse double minute 2 and adenoviruses encoding p53

Graat, Harm C.A.; Carette, Jan E.; Schagen, Frederik H.E.; Vassilev, Lyubomir T.; Gerritsen, Winald R.; Kaspers, Gertjan J. L.; Wuisman, P.; Beusechem, Victor W. van

doi:10.1158/1535-7163.mct-06-0631

Cited by 30 publications

(25 citation statements)

References 29 publications

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“…Extensive efforts have been made in recent years to restore PTEN in cancer therapy. For example, the introduction of wild-type PTEN by viral vectors; the aerosol delivery of nonviral vector, urocanic acid-modified, chitosan-mediated PTEN; and the introduction of cell permeable, recombinant, wild-type PTEN into cells by fusing PTEN with a cell permeable protein transduction domain (PTD) demonstrated the possibilities to further develop these strategies [48][49]. Great advances have been also made in the development of molecularly targeted therapies targeting the kinases of the PI3K-Akt-mTOR network.…”

Section: Targeting Pi3k-akt-mtor Sensitizes Cancer Cells To Chemothermentioning

confidence: 99%

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang¹,

Huang²,

Zhang³

2014

Cellular and Molecular Biology Letters

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telangiectasia and Rad3-related; CDK4/6 -cyclin-dependent kinase 4/6; Chk1 -checkpoint kinase 1; Chk2 -checkpoint kinase 2; FA -Fanconi anemia; FANCD2 -Fanconi anemia group D2; FANCI -Fanconi anemia group I; HR -homologous recombination; ICL -DNA interstrand crosslinker; IGFBP-3 -insulin-like growth factor binding protein 3; IRS -insulin receptor substrate; MAPKmitogen-activated protein kinase; mTOR -mammalian target of rapamycin; NERnucleotide excision repair; PH -pleckstrin homology; PI3K -phosphoinositide 3-kinase; PIP2 -phosphatidylinositol 4,5-phosphate; PIP3 -phosphatidylinositol 3,4,5-trisphosphate; PTEN -phosphatase/tensin homolog deleted on chromosome 10; Rb -retinoblastoma; Rheb -Ras-homolog enriched in brain; RNR -ribonucleotide reductase; RTK -receptor tyrosine kinase; TLS -translesion DNA synthesis; TSC2 -tuberous sclerosis complex-2 Abstract: Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2

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Section: Targeting Pi3k-akt-mtor Sensitizes Cancer Cells To Chemothermentioning

confidence: 99%

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang¹,

Huang²,

Zhang³

2014

Cellular and Molecular Biology Letters

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“…Non-proliferative states are found in quiescent cells, cells with stem-cell like phenotypes and dormant cells [29][30][31]. NBDHEX [80] GST NBDHEX [79,80] V Increased DNA repair (ATM/DNA-PK) γH2AX [81] APE-1 [82] ERCC2 or XPD gene [83] γH2AX si-γH2AX [81] γH2AX miR-138 overexpression [81] APE-1 si-APE1 [82] VI Apoptosis resistance p53/BAX/NOXA/PUMA/p53AIP1 [43,55] p53/MDM2 Nutlin(-3a) [105,106] Fas [84,[90][91][92][93] Fas IL-12 [84,91,93] Fas Gemcitabine [21,90] Fas Liposomal MTP-PE [97,[107][108][109][110][111][112][113] FasL Ifosfamide [84,90] NF-κB/Survivin [64] JNK/c-Jun/AP-1 [65,94] cancer stem cells that have characteristics similar to normal/ healthy stem cells but give rise to cell populations that do not mature into fully differentiated cells but rather cells that hold the ability to divide infinitely, thus producing cancer cells. Many solid tumours are known to contain small populations of stem-like cells, or cancer stem cells [32,33].…”

Section: Non-proliferative Statementioning

confidence: 99%

“…In OS, inactivating p53 mutations are encountered, as well as increased expression of negative regulators of OS such as mouse double minute 2 (MDM2) protein [15,43,55,74,105,106]. MDM2 is a ligase that binds to p53 and subsequently promotes its degradation.…”

Section: Apoptosis Resistancementioning

confidence: 99%

“…MDM2 is a ligase that binds to p53 and subsequently promotes its degradation. Nutlin3a (Nutlin in short) is a small molecule inhibitor of MDM2 by binding at the p53 binding-site thereby rendering MDM2 inactive through prevention of MDM2-p53 binding [105,106]. Previous work from our group demonstrated that treatment with Nutlin induced cell death in p53 wild-type OS cells.…”

Section: Apoptosis Resistancementioning

confidence: 99%

“…Previous work from our group demonstrated that treatment with Nutlin induced cell death in p53 wild-type OS cells. Combination treatment of Nutlin with an adenovirus introducing exogenous p53 further augmented tumour cell kill [105]. Thus, in principle, combining conventional therapies with Nutlin could potentially increase therapeutic efficacy.…”

Section: Apoptosis Resistancementioning

confidence: 99%

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Mechanisms of therapy resistance in osteosarcoma: a review

Boer¹,

Royen²,

Helder³

2013

Oncol Discov

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Therapy resistance remains a challenge in the treatment for osteosarcoma (OS). By studying therapy resistance and gaining biological understanding of resistance in OS, novel treatment targets to sensitise OS could potentially be discovered. The aim of this review is to give an overview of the mechanisms of resistance employed by OS cells after cytotoxic treatment, the key molecules involved in therapy resistance combined with the (pre)clinical research performed on this subject in a search to discover means to overcome therapy resistance and thus improve treatment efficacy for OS.

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Chromosome instability and tumor lethality suppression in carcinogenesis

Shen¹,

Zhou²,

Zhan³

et al. 2008

J of Cellular Biochemistry

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The maintenance and survival of each organism depends on its genome integrity. Alterations of essential genes, or aberrant chromosome number and structure lead to cell death. Paradoxically, cancer cells, especially in solid tumors, contain somatic gene mutations and are chromosome instability (CIN), suggesting a mechanism that cancer cells have acquired to suppress the lethal mutations and/or CIN. Herein we will discuss a tumor lethality suppression concept based on the studies of yeast genetic interactions and transgenic mice. During the early stages of the multistep process of tumorigenesis, incipient cancer cells probably have adopted genetic and epigenetic alterations to tolerate the lethal mutations of other genes that ensue, and to a larger extent CIN. In turn, CIN mediated massive gain and loss of genes provides a wider buffer for further genetic reshuffling, resulting in cancer cell heterogeneity, drug resistance and evasion of oncogene addiction, thus CIN may be both the effector and inducer of tumorigenesis. Accordingly, interfering with tumor lethality suppression could lead to cancer cell death or growth defects. Further validation of the tumor lethality suppression concept would help to elucidate the role of CIN in tumorigenesis, the relationship between CIN and somatic gene mutations, and would impact the design of anticancer drug development.

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Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of mouse double minute 2 and adenoviruses encoding p53

Cited by 30 publications

References 29 publications

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Mechanisms of therapy resistance in osteosarcoma: a review

Chromosome instability and tumor lethality suppression in carcinogenesis

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