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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 viability and proliferation in hepatocellular carcinoma cellsPLC/PRF/5 (A), Hep3B (B), HepG2 (C) and HuH7 (D) cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours, and cell viability was measured by MTT assay (left). The combination index (CI) values were calculated by CompuSyn software (right). CI values <1 represent synergism, and the numbers reflect the corresponding data points (left). (E) Cells were treated with indicated agents for 72 hours, BrdU was added during last 2 h of incubation period and the assay was performed by using a Proliferation Assay kit according to the manufacturer's instructions (Millipore, Billerica, MA). Each value represents the mean ± SD (n = 3). **, P < 0.01 compared with the control group. #, P < 0.01, compared with the sorafenib or DE605 group.
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Figure 2: Effects of sorafenib in combination with DE605 on cell viability and proliferation in hepatocellular carcinoma cellsPLC/PRF/5 (A), Hep3B (B), HepG2 (C) and HuH7 (D) cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours, and cell viability was measured by MTT assay (left). The combination index (CI) values were calculated by CompuSyn software (right). CI values <1 represent synergism, and the numbers reflect the corresponding data points (left). (E) Cells were treated with indicated agents for 72 hours, BrdU was added during last 2 h of incubation period and the assay was performed by using a Proliferation Assay kit according to the manufacturer's instructions (Millipore, Billerica, MA). Each value represents the mean ± SD (n = 3). **, P < 0.01 compared with the control group. #, P < 0.01, compared with the sorafenib or DE605 group.

Mentions: To investigate the effect of the combined treatment in experimental models of HCC, four hepatocellular carcinoma cell lines were treated with different concentrations of sorafenib in the presence or absence of DE605 for 72 hours, and cell viability was determined by MTT assay. Our results revealed that DE605 significantly and concentration-dependently enhanced sorafenib-mediated cytotoxicity in PLC/PRF/5 cells (Fig. 2A). To explore whether the combined treatment had a synergistic impact on cell viability, the combination index values of each dose were calculated by the CompuSyn software. The results revealed that DE605 exhibited a synergistic effect in combination with sorafenib at low concentrations (0.5 and 1.0 μM) (Fig. 2A, right). In addition, to confirm these results, PLC/PRF/5 cells were treated with sorafenib and a previously reported c-MET selective inhibitor tivantinib (ARQ 197) [27] for 72 hours, cell viability was determined by MTT assay and combination index values was calculated. Interestingly, the results revealed that tivantinib also exhibited a synergistic effect in combination with sorafenib at low concentrations (0.25 and 0.5 μM), which is similar to those obtained in sorafenib combination with DE605 (supplemental Fig. S2B). Moreover, the synergistic effect between DE605 and sorafenib were also observed in Hep3B, HepG2 and HuH7 cells, indicating that this was not a cell line–specific effect (Fig. 2B, 2C and 2D). Furthermore, the combined treatment significantly enhanced the antiproliferative effects in all four tested cell lines as evidenced by BrdU incorporation assay (Fig. 2E). Taken together, our results indicate that DE605 combination with sorafenib synergistically increased cytotoxicity and improved the anti-proliferative effects consistently in different hepatocellular carcinoma cell lines.


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 viability and proliferation in hepatocellular carcinoma cellsPLC/PRF/5 (A), Hep3B (B), HepG2 (C) and HuH7 (D) cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours, and cell viability was measured by MTT assay (left). The combination index (CI) values were calculated by CompuSyn software (right). CI values <1 represent synergism, and the numbers reflect the corresponding data points (left). (E) Cells were treated with indicated agents for 72 hours, BrdU was added during last 2 h of incubation period and the assay was performed by using a Proliferation Assay kit according to the manufacturer's instructions (Millipore, Billerica, MA). Each value represents the mean ± SD (n = 3). **, P < 0.01 compared with the control group. #, P < 0.01, compared with the sorafenib or DE605 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Effects of sorafenib in combination with DE605 on cell viability and proliferation in hepatocellular carcinoma cellsPLC/PRF/5 (A), Hep3B (B), HepG2 (C) and HuH7 (D) cells were treated with various concentrations of sorafenib in combination with DE605 for 72 hours, and cell viability was measured by MTT assay (left). The combination index (CI) values were calculated by CompuSyn software (right). CI values <1 represent synergism, and the numbers reflect the corresponding data points (left). (E) Cells were treated with indicated agents for 72 hours, BrdU was added during last 2 h of incubation period and the assay was performed by using a Proliferation Assay kit according to the manufacturer's instructions (Millipore, Billerica, MA). Each value represents the mean ± SD (n = 3). **, P < 0.01 compared with the control group. #, P < 0.01, compared with the sorafenib or DE605 group.
Mentions: To investigate the effect of the combined treatment in experimental models of HCC, four hepatocellular carcinoma cell lines were treated with different concentrations of sorafenib in the presence or absence of DE605 for 72 hours, and cell viability was determined by MTT assay. Our results revealed that DE605 significantly and concentration-dependently enhanced sorafenib-mediated cytotoxicity in PLC/PRF/5 cells (Fig. 2A). To explore whether the combined treatment had a synergistic impact on cell viability, the combination index values of each dose were calculated by the CompuSyn software. The results revealed that DE605 exhibited a synergistic effect in combination with sorafenib at low concentrations (0.5 and 1.0 μM) (Fig. 2A, right). In addition, to confirm these results, PLC/PRF/5 cells were treated with sorafenib and a previously reported c-MET selective inhibitor tivantinib (ARQ 197) [27] for 72 hours, cell viability was determined by MTT assay and combination index values was calculated. Interestingly, the results revealed that tivantinib also exhibited a synergistic effect in combination with sorafenib at low concentrations (0.25 and 0.5 μM), which is similar to those obtained in sorafenib combination with DE605 (supplemental Fig. S2B). Moreover, the synergistic effect between DE605 and sorafenib were also observed in Hep3B, HepG2 and HuH7 cells, indicating that this was not a cell line–specific effect (Fig. 2B, 2C and 2D). Furthermore, the combined treatment significantly enhanced the antiproliferative effects in all four tested cell lines as evidenced by BrdU incorporation assay (Fig. 2E). Taken together, our results indicate that DE605 combination with sorafenib synergistically increased cytotoxicity and improved the anti-proliferative effects consistently in different hepatocellular carcinoma cell lines.

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