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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

Effects of sorafenib in combination with DE605 on cell-cycle progression in PLC/PRF/5 cells(A) PLC/PRF/5 cells were treated with the indicated drugs for 72 hours, and cell-cycle distribution was analyzed by flow cytometry. (B) Statistical analysis of sub-G1 phase in PLC/PRF/5 cells exposed to DMSO, sorafenib alone, DE605 alone, or in sorafenib/DE605 combination. Data, mean ± SD (n = 3).
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Figure 3: Effects of sorafenib in combination with DE605 on cell-cycle progression in PLC/PRF/5 cells(A) PLC/PRF/5 cells were treated with the indicated drugs for 72 hours, and cell-cycle distribution was analyzed by flow cytometry. (B) Statistical analysis of sub-G1 phase in PLC/PRF/5 cells exposed to DMSO, sorafenib alone, DE605 alone, or in sorafenib/DE605 combination. Data, mean ± SD (n = 3).

Mentions: As sorafenib and c-Met inhibitors reportedly induce apoptosis in cancer cells [8, 28], we examined the impact of our drug combination on programmed cell death. First, the effect of co-administration of DE605 and sorafenib on cell-cycle distribution was analyzed by flow cytometric analysis. As shown in Fig. 3A, no appreciable cell-cycle arrest was observed after sorfenib or DE605 treatment alone. However, the combined treatment significantly enhanced the percentage of sub-G1 phase cells over that seen in cells treated with either drug alone, suggesting that apoptosis is the main cause of cell death in the co-treated PLC/PRF/5 cells (Fig. 3B).


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)

Effects of sorafenib in combination with DE605 on cell-cycle progression in PLC/PRF/5 cells(A) PLC/PRF/5 cells were treated with the indicated drugs for 72 hours, and cell-cycle distribution was analyzed by flow cytometry. (B) Statistical analysis of sub-G1 phase in PLC/PRF/5 cells exposed to DMSO, sorafenib alone, DE605 alone, or in sorafenib/DE605 combination. Data, mean ± SD (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Effects of sorafenib in combination with DE605 on cell-cycle progression in PLC/PRF/5 cells(A) PLC/PRF/5 cells were treated with the indicated drugs for 72 hours, and cell-cycle distribution was analyzed by flow cytometry. (B) Statistical analysis of sub-G1 phase in PLC/PRF/5 cells exposed to DMSO, sorafenib alone, DE605 alone, or in sorafenib/DE605 combination. Data, mean ± SD (n = 3).
Mentions: As sorafenib and c-Met inhibitors reportedly induce apoptosis in cancer cells [8, 28], we examined the impact of our drug combination on programmed cell death. First, the effect of co-administration of DE605 and sorafenib on cell-cycle distribution was analyzed by flow cytometric analysis. As shown in Fig. 3A, no appreciable cell-cycle arrest was observed after sorfenib or DE605 treatment alone. However, the combined treatment significantly enhanced the percentage of sub-G1 phase cells over that seen in cells treated with either drug alone, suggesting that apoptosis is the main cause of cell death in the co-treated PLC/PRF/5 cells (Fig. 3B).

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