Abstract
To evaluated the effect of the gambogic acid (GA), one of the effective components of Garcinia, in combination with a new multi-targeted oral medication, sunitinib (SU) on renal cancer cell proliferation in vitro and on tumor growth in vivo. After treatment with GA or SU, either alone or in combination, MTT and FACS analysis were used to examine cell viability and cycle distribution of the renal carcinoma cell lines 786-0 and Caki-1. Western blotting was employed to examine the expression of proteins related to the cell cycle and vascular formation. Furthermore, a xenograft model was applied to study the antitumor efficacy of SU or GA alone or in combination, with immunohistochemistry to detect expression of proteins related to xenograft growth and angiogenesis. Western blotting was used to examine NF-?B signaling pathway elements in xenografts. Treatment of 786-0 and Caki-1 cells with GA or SU resulted in decreased tumor cell proliferation, especially with joint use. Cells accumulated more strongly in the sub-G1 phase after joint treatment with GA and SU than treatment of GA and SU alone. Western blotting arrays showed 1 protein significantly upregulated, 2 proteins downregulated, and 2 proteins unchanged. Moreover, combined use of GA and SU inhibited the growth and angiogenesis of xenografts generated from Caki-1 significantly. Immunohistochemistry arrays showed downregulation of the expression of proteins promoting xenograft growth and angiogenesis, and Western blotting showed inhibition of the NF-?B signaling pathway after treatment by GA alone and in combination with SU in xenografts. Our results show that the joint use of GA and SU can provide greater antitumor efficacy compared to either drug alone and thus may offer a new treatment strategy for renal cell carcinoma.
Highlights
Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies
Not all patients received SU treatment receive complete responses and most of the patients progress during therapy at last (Rini et al, 2009),and at the same time, compared with other single target drugs, SU may lead to more potential adverse reaction due to its inhibition of multiple target molecular mechanism
New therapy strategies are urgently needed to get complete responses and improve patient outcomes. It seems that combination therapies of SU with other targeted drugs, such as bevacizumab, sorafenib, gefitinib (Dudek et al, 2009; Feldman et al, 2009; Motzer et al, 2010), could be more effective than single targeted therapies,whereas there is no study has evaluated the combination with gambogic acid (GA)
Summary
Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies It accounts for 2–3% of cancers worldwide (Jemal et al, 2009). With the depth of kidney cancer molecular mechanisms to understand, there have been new molecular targeted therapy drugs which have revolutionized the therapy of metastatic RCC. Among those agents, sunitinib(SU) is a novel small molecule targets of tyrosine kinase inhibitors for RCC to be approved by the FDA in December 2005,it can inhibit vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor receptor with both antiangiogenic and antitumoral activities. For further improvement of prognosis, it seems that combination of chemotherapy drugs with different mechanisms are required, and combination therapies of SU with other targeted drugs ,such as bevacizumab, sorafenib, gefitinib have the potential to be more effective than single targeted therapies (Dudek et al, 2009; Feldman et al, 2009; Motzer et al, 2010)
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