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- Felth, Jenny, 1979-, et al.
(författare)
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Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
- 2013
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 31:3, s. 587-598
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.
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| 2. |
- Hernlund, Emma, et al.
(författare)
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The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy
- 2012
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 48:3, s. 396-406
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems.METHODS:We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis.RESULTS:Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin-proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®).CONCLUSIONS:The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours.
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