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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

Antitumor activity of DE605 plus sorafenib in a PLC/PRF/5 xenograft modelAthymic nude mice bearing subcutaneously established PLC/PRF/5 xenograft tumors were randomized to four groups (n = 7), and received the indicated treatments by gavage. (A) tumor volumes were measured twice per week and the curves of tumor growth volume was expressed as mean ± SD. **, P< 0.01 compared with the control group, #, P< 0.01, compared with the sorafenib or DE605 group. (B) body weights were measured twice per week, and are expressed as mean ± SD. (C-D) IHC analysis of intratumoral proliferation in PLC/PRF/5 xenograft tumors. Tumors were harvested and paraffin-embedded tumor tissues were subjected to immunostaining for Ki-67 (C) and TUNEL (D). Images were captured by Zeiss Axioskop-2 microscope under 200× magnification. Scale bar, 100 μm.
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Figure 6: Antitumor activity of DE605 plus sorafenib in a PLC/PRF/5 xenograft modelAthymic nude mice bearing subcutaneously established PLC/PRF/5 xenograft tumors were randomized to four groups (n = 7), and received the indicated treatments by gavage. (A) tumor volumes were measured twice per week and the curves of tumor growth volume was expressed as mean ± SD. **, P< 0.01 compared with the control group, #, P< 0.01, compared with the sorafenib or DE605 group. (B) body weights were measured twice per week, and are expressed as mean ± SD. (C-D) IHC analysis of intratumoral proliferation in PLC/PRF/5 xenograft tumors. Tumors were harvested and paraffin-embedded tumor tissues were subjected to immunostaining for Ki-67 (C) and TUNEL (D). Images were captured by Zeiss Axioskop-2 microscope under 200× magnification. Scale bar, 100 μm.

Mentions: To evaluate whether the synergistic effect of DE605 plus sorafenib could be clinically relevant, we examined the antitumor activity of this cotreatment in athymic nude mice bearing established PLC/PRF/5 tumor xenografts. As seen in Fig. 6A, Oral treatment with sorafenib or DE605 alone for 28 days resulted in a modest tumor growth inhibition (TGI) in the nude mice (17.3% and 37.3%, respectively) compared with the control group. DE605 in combination with sorafenib significantly suppressed tumor growth, with TGI of 59.7%. In addition, the cotreatment exhibited significant difference compared with sorafenib or DE605 alone in the PLC/PRF/5 xenograft model. Moreover, the average body weights of the mice were comparable throughout the experimental period. As seen in Fig. 6B, there was no difference in body weight in treatment groups compared with the control group. These data suggest that the treatment in these studies is not associated with apparent gross toxicity.


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)

Antitumor activity of DE605 plus sorafenib in a PLC/PRF/5 xenograft modelAthymic nude mice bearing subcutaneously established PLC/PRF/5 xenograft tumors were randomized to four groups (n = 7), and received the indicated treatments by gavage. (A) tumor volumes were measured twice per week and the curves of tumor growth volume was expressed as mean ± SD. **, P< 0.01 compared with the control group, #, P< 0.01, compared with the sorafenib or DE605 group. (B) body weights were measured twice per week, and are expressed as mean ± SD. (C-D) IHC analysis of intratumoral proliferation in PLC/PRF/5 xenograft tumors. Tumors were harvested and paraffin-embedded tumor tissues were subjected to immunostaining for Ki-67 (C) and TUNEL (D). Images were captured by Zeiss Axioskop-2 microscope under 200× magnification. Scale bar, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Antitumor activity of DE605 plus sorafenib in a PLC/PRF/5 xenograft modelAthymic nude mice bearing subcutaneously established PLC/PRF/5 xenograft tumors were randomized to four groups (n = 7), and received the indicated treatments by gavage. (A) tumor volumes were measured twice per week and the curves of tumor growth volume was expressed as mean ± SD. **, P< 0.01 compared with the control group, #, P< 0.01, compared with the sorafenib or DE605 group. (B) body weights were measured twice per week, and are expressed as mean ± SD. (C-D) IHC analysis of intratumoral proliferation in PLC/PRF/5 xenograft tumors. Tumors were harvested and paraffin-embedded tumor tissues were subjected to immunostaining for Ki-67 (C) and TUNEL (D). Images were captured by Zeiss Axioskop-2 microscope under 200× magnification. Scale bar, 100 μm.
Mentions: To evaluate whether the synergistic effect of DE605 plus sorafenib could be clinically relevant, we examined the antitumor activity of this cotreatment in athymic nude mice bearing established PLC/PRF/5 tumor xenografts. As seen in Fig. 6A, Oral treatment with sorafenib or DE605 alone for 28 days resulted in a modest tumor growth inhibition (TGI) in the nude mice (17.3% and 37.3%, respectively) compared with the control group. DE605 in combination with sorafenib significantly suppressed tumor growth, with TGI of 59.7%. In addition, the cotreatment exhibited significant difference compared with sorafenib or DE605 alone in the PLC/PRF/5 xenograft model. Moreover, the average body weights of the mice were comparable throughout the experimental period. As seen in Fig. 6B, there was no difference in body weight in treatment groups compared with the control group. These data suggest that the treatment in these studies is not associated with apparent gross toxicity.

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