Developmental Therapeutics Program at the NCI: molecular target and drug discovery process

Monga, Manish; Sausville, Edward A.

doi:10.1038/sj.leu.2402464

Cited by 126 publications

(77 citation statements)

References 20 publications

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“…We demonstrate that endothelial cells transformed by vGPCR were exquisitely sensitive to the antiproliferative properties of UCN-01, a chemotherapeutic drug recently documented to potently inhibit the Akt modulator, 3Ј-phosphoinositide-dependent protein kinase 1 (35,47,48). The antiproliferative effects of UCN-01 had an average IC 50 concentration of Ϸ9 nM, which is significantly lower than that estimated for the NCI 60 cancer cell line panel (Ϸ37 nM) (49), and well within the therapeutic levels of unbound UCN-01 easily achieved in humans (Ϸ110 nM) (36). We further observed a significant antitumor effect after only one treatment cycle of UCN-01, which was sustained for 10 d following initiation of treatment.…”

Section: Discussionmentioning

confidence: 72%

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Sodhi

Montaner

Patel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

140

132

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We have recently engineered an in vivo endothelial cell-specific retroviral gene transfer system and found that a single Kaposi's sarcoma (KS)-associated herpesvirus͞human herpesvirus 8 gene encoding a G protein-coupled receptor (vGPCR), is sufficient to induce KS-like tumors in mice. By using this system, we show here that the Akt signaling pathway plays a central role in vGPCR oncogenesis. Indeed, a constitutively active Akt was sufficient to induce benign hemangiomas in mice, whereas heterozyogosity for PTEN (the phosphatase and tension homologue deleted on chromosome 10), modestly enhancing basal Akt activity, dramatically enhanced vGPCR sarcomagenesis. Examination of KS biopsies from AIDS patients revealed active Akt as a prominent feature, supportive of a role for Akt in human Kaposi's sarcomagenesis. By using a vGPCR agonist-dependent mutant, we further establish constitutive activity as a requirement for vGPCR sarcomagenesis, validating targeted inhibition of key vGPCR signaling pathways as an approach for preventing its oncogenic potential. These observations prompted us to explore the efficacy of inhibiting Akt activation as a molecular approach to KS treatment. Pharmacological inhibition of the Akt pathway with the chemotherapeutic agent 7-hydroxystaurosporine prevented proliferation of vGPCR-expressing endothelial cells in vitro and inhibited their tumorigenic potential in vivo. Both were associated with a decrease in Akt activity. These results identify Akt as an essential player in vGPCR sarcomagenesis and demonstrate the therapeutic potential of drugs targeting this pathway in the treatment of KS.human herpesvirus 8 ͉ Kaposi's sarcoma-associated herpesvirus ͉ 7-hydroxystaurosporine

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Section: Discussionmentioning

confidence: 72%

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Sodhi

Montaner

Patel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

140

132

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“…Cancer cells exposed for 36 and 48 h to sunitinib or everolimus were subjected to a recovery experiment by replacing the drugcontaining medium with fresh medium and subsequently allowing them to recover inside the incubator for 36 h. The incubation period for the recovery assay was selected based on the suggested doubling time for Caki-1 cells as provided by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) [19].…”

Section: Recovery Assaymentioning

confidence: 99%

Cytotoxic activity of sunitinib and everolimus in Caki-1 renal cancer cells is accompanied by modulations in the expression of apoptosis-related microRNA clusters and BCL2 family genes

Papadopoulos

Yousef

Scorilas

2015

Biomedicine & Pharmacotherapy

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“…The value of any preclinical model ultimately depends on its ability to accurately predict clinical response. Therefore, a new anticancer drug is usually tested in three stages: in vitro cell screening, in vivo animal models, and clinical trials [14].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the therapeutic efficacy of tripeptide tyroserleutide (YSL) for human hepatocarcinoma by in vivo hollow fiber assay

Liu

Lü

et al. 2008

Invest New Drugs

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Tyroserleutide (YSL), extracted from spleen of pigs, is a tripeptide that has shown therapeutic efficacy in an experimental BEL-7402 human hepatocarcinoma model. The hollow fiber assay (HFA) is a solid tumor model for large-scale screening of potential anticancer compounds that minimizes expenditures of materials, time, and money. Tumor cells are cultivated within biocompatible, semipermeable hollow fibers, which are implanted in immunosuppressed mice. In this study, the HFA was used to investigate the therapeutic efficacy of YSL for human hepatocarcinoma. In vitro effects of YSL on human hepatocarcinoma cell lines BEL-7402, SMMC-7721, Hep3B, HepG2, and SK-HEP-1 were assayed by the MTS method. In vivo effects of YSL on the five human hepatocarcinoma cell lines were assayed by HFA. Mice implanted with tumor cells in hollow fibers were treated with YSL, and the effects of YSL on tumor cell populations were assessed by MTT assay. YSL significantly inhibited the proliferation of the five human hepatocarcinoma, both in vitro and in vivo (P < 0.05). The HFA is a rapid, accurate, and economical method for evaluating the inhibitory effects of drugs on different tumor cells in vivo. These results support the clinical application of YSL for treatment of human hepatocarcinoma.

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Developmental Therapeutics Program at the NCI: molecular target and drug discovery process

Cited by 126 publications

References 20 publications

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor

Cytotoxic activity of sunitinib and everolimus in Caki-1 renal cancer cells is accompanied by modulations in the expression of apoptosis-related microRNA clusters and BCL2 family genes

Evaluation of the therapeutic efficacy of tripeptide tyroserleutide (YSL) for human hepatocarcinoma by in vivo hollow fiber assay

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