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Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma.

Jiang X, Feng K, Zhang Y, Li Z, Zhou F, Dou H, Wang T - Oncotarget (2015)

Bottom Line: Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism.Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice.Importantly, no obvious weight loss (toxicity) was detected.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.

ABSTRACT
Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.

No MeSH data available.


Related in: MedlinePlus

Effect of sorafenib plus DE605 on LDH activity, nucleosome formation and the apoptosis-related proteins in PLC/PRF/5 cells(A) PLC/PRF/5 cells were exposed to indicated drugs for 72 hours. LDH acticity in cell supernatants or lysates was analyzed by the CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI) according to manufacturer's protocol. (B) PLC/PRF/5 cells were treated with sorafenib (4 μM) alone or in combination with DE605 (1 μM) for 72 hours. Nucleosome formation was measured using the Cell Death ELISA Kit (Roche Applied Science). Data, mean ± SD (n = 3; **, P < 0.01 compared with the control group). (C) Cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours. (D) Cells were exposed to sorafenib (Sor, 4 μM) in combination with DE605 (1 μM) in the presence or absence of zVAD–FMK for 72 hours. Whole-cell lysates were collected and subjected to Western blot analysis with the indicated antibodies.
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Figure 4: Effect of sorafenib plus DE605 on LDH activity, nucleosome formation and the apoptosis-related proteins in PLC/PRF/5 cells(A) PLC/PRF/5 cells were exposed to indicated drugs for 72 hours. LDH acticity in cell supernatants or lysates was analyzed by the CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI) according to manufacturer's protocol. (B) PLC/PRF/5 cells were treated with sorafenib (4 μM) alone or in combination with DE605 (1 μM) for 72 hours. Nucleosome formation was measured using the Cell Death ELISA Kit (Roche Applied Science). Data, mean ± SD (n = 3; **, P < 0.01 compared with the control group). (C) Cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours. (D) Cells were exposed to sorafenib (Sor, 4 μM) in combination with DE605 (1 μM) in the presence or absence of zVAD–FMK for 72 hours. Whole-cell lysates were collected and subjected to Western blot analysis with the indicated antibodies.

Mentions: Meanwhile, the possibility of necrotic effect was excluded by examining LDH leakage in the supernatants of drug-treated PLC/PRF/5 cells (Fig. 4A). To confirm this effect, nucleosome formation (representing DNA fragmentation) was determined in drug-treated cells. The results showed that DE605 dramatically enhanced sorafenib-induced nucleosome formation in PLC/PRF/5 cells (Fig. 4B).


Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma.

Jiang X, Feng K, Zhang Y, Li Z, Zhou F, Dou H, Wang T - Oncotarget (2015)

Effect of sorafenib plus DE605 on LDH activity, nucleosome formation and the apoptosis-related proteins in PLC/PRF/5 cells(A) PLC/PRF/5 cells were exposed to indicated drugs for 72 hours. LDH acticity in cell supernatants or lysates was analyzed by the CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI) according to manufacturer's protocol. (B) PLC/PRF/5 cells were treated with sorafenib (4 μM) alone or in combination with DE605 (1 μM) for 72 hours. Nucleosome formation was measured using the Cell Death ELISA Kit (Roche Applied Science). Data, mean ± SD (n = 3; **, P < 0.01 compared with the control group). (C) Cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours. (D) Cells were exposed to sorafenib (Sor, 4 μM) in combination with DE605 (1 μM) in the presence or absence of zVAD–FMK for 72 hours. Whole-cell lysates were collected and subjected to Western blot analysis with the indicated antibodies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494942&req=5

Figure 4: Effect of sorafenib plus DE605 on LDH activity, nucleosome formation and the apoptosis-related proteins in PLC/PRF/5 cells(A) PLC/PRF/5 cells were exposed to indicated drugs for 72 hours. LDH acticity in cell supernatants or lysates was analyzed by the CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI) according to manufacturer's protocol. (B) PLC/PRF/5 cells were treated with sorafenib (4 μM) alone or in combination with DE605 (1 μM) for 72 hours. Nucleosome formation was measured using the Cell Death ELISA Kit (Roche Applied Science). Data, mean ± SD (n = 3; **, P < 0.01 compared with the control group). (C) Cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours. (D) Cells were exposed to sorafenib (Sor, 4 μM) in combination with DE605 (1 μM) in the presence or absence of zVAD–FMK for 72 hours. Whole-cell lysates were collected and subjected to Western blot analysis with the indicated antibodies.
Mentions: Meanwhile, the possibility of necrotic effect was excluded by examining LDH leakage in the supernatants of drug-treated PLC/PRF/5 cells (Fig. 4A). To confirm this effect, nucleosome formation (representing DNA fragmentation) was determined in drug-treated cells. The results showed that DE605 dramatically enhanced sorafenib-induced nucleosome formation in PLC/PRF/5 cells (Fig. 4B).

Bottom Line: Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism.Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice.Importantly, no obvious weight loss (toxicity) was detected.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.

ABSTRACT
Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.

No MeSH data available.


Related in: MedlinePlus