ECE2014 Oral Communications IGF-1 and Thyroid Basic (5 abstracts)
Targeting the insulin-like growth factor 1 (IGF1R) and insulin (IR) receptor with a dual IGF1R/IR inhibitor, OSI-906, to potentiate mTOR inhibitor effects in experimental models of hepatocellular carcinoma (HCC)
Claudia Pivonello 1 , Mariarosaria Negri 1 , Maria Cristina De Martino 1 , Cristina de Angelis 1 , Maria Napolitano 2 , Francesco Izzo 2 , Annamaria Colao 1 , Leo J. Hofland 3 & Rosario Pivonello 1
1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, Naples, Italy; 2Department of Surgical Oncology, Hepatobiliary Surgery Unit, National Cancer Institute, G. Pascale Foundation, Naples, Italy; 3Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
The mTOR and IGF/insulin pathways are frequently dysregulated in HCC. Antitumoral activity of mTOR inhibitors (mTORi) has been demonstrated in experimental models but in early clinical studies mTORi alone have shown modest antitumoral activity. IGF/insulin-dependent Akt activation, via IGF1R and IR, has been suggested as potential mechanism for mTORi resistance. This study aimed at evaluating the expression of mTOR and IGF/insulin pathway components and the effects of mTORi alone and in combination with the dual IGF1R/IR inhibitor, OSI-906, in human HCC cell lines HepG2 and HuH7. Expression of mTOR and IGF/insulin pathways components was evaluated by qRT-PCR. The effect of rapamycin (RAP), OSI-906 and combined treatment (CT, RAP 10−10M plus OSI-906 10−6M) was evaluated after 3 days on: cell proliferation (DNA assay), cell secretion (AFP concentrations, CLIA assay), cell cycle (FACS), cell migration (Scratch assay), cell invasion (Matrigel assay), and signaling pathways (WB). Both cell lines express mTOR components, IGF1R and IR and high levels of IGF2. Both RAP (P<0.0001) and OSI-906 (P<0.01) inhibited cell proliferation; CT had additive effects (P<0.001). Similarly, both drugs significantly suppressed AFP secretion with no additive effect of CT. OSI-906 (P<0.01) but not by RAP blocked cell cycle in G0/G1, with CT showing additive effects (P<0.001). In HuH7, OSI-906 (P<0.001) but not RAP inhibited cell migration with CT showing additive effects (P<0.0001). RAP (P<0.0001), OSI-906 (P<0.0001) and CT (P<0.0001) blocked cell invasion. HepG2 did not show invasion capability and both RAP and OSI-906 did not have effect on migration. Preliminary data on cell signalling demonstrated inhibition of ERK1/2, Akt and p70S6k activation after CT in HepG2. In conclusion, the results of the current study provide evidence that the combination of RAP and OSI-906 has an additive inhibitory effect on cell proliferation and cell cycle block by preventing Akt activation in experimental models of HCC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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