Apatinib

Apatinib （YN968D1）is a potent inhibior of the VEGF signaling pathway with the IC50 value of 1nM for VEGFR-2 in in vitro enzyme experiments [1].

In vitro, Apatinib has shown the inhibition of tyrosine kinase activities with the IC50 values of 0.013μM, 0.429μM and 0.53μM for Ret, c-kit and c-src, respectively. In addition, Apatinib has been revealed to have no significant effects in EGFR, Her-2 or FGFR1 in concentrations up to 10μM. Apart from these, Apatinib has been reported to inhibit the growth factor-stimulated receptor phosphorylation at the cellular level. Furthermore, Apatinib has also reported to slightly inhibitor proliferation of HUVEC by 20% FBS with the IC50 value of 23.4μM and significantly inhibit stimulated by 20ng/mL VEGF with the IC50 value of 0.17μM. Once-daily oral administration of Apatinib has been noted to produce a dose-dependent inhibition of tumor growth in human tumor xenografts in immunodeficient mice [1]

References:
[1] Tian S1, Quan H, Xie C, Guo H, Lü F, Xu Y, Li J, Lou L. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011 Jul;102(7):1374-80.

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[Inhibitory effect of apatinib on HCT-116 cells and its mechanism].[Pubmed:28377354]

Nan Fang Yi Ke Da Xue Xue Bao. 2017 Mar 20;37(3):367-372.

OBJECTIVE: To investigate the inhibitory effects of Apatinib on colorectal carcinoma HCT-116 cells in vitro and the signaling pathways involved. METHODS: The cytotoxicity of different concentrations (0, 0.5, 1, 1.5, and 2 micromol/L) of Apatinib in HCT-116 cells was assessed by MTT assay, using capecitabine as the positive control. The apoptosis rate of Apatinib-treated HCT-116 cells was detected using flow cytometry, and the expressions of Bcl-2, Bax, and caspase-3 were determined with quantitative real-time PCR and Western blotting. The effect of Apatinib on the expressions of Akt, pAkt, Erk1/2 and pErk1/2 in HCT-116 cells was evaluated using Western blotting. RESULTS: Apatinib significantly inhibited the proliferation of HCT-116 cells in a concentration-dependent manner with an IC50 value of 1.335 micromol/L. Flow cytometric analysis showed that Apatinib significantly increased the apoptotic rate of HCT-116 cells dose-dependently. Apatinib induced the expression of the pro-apoptotic genes Bax and caspase-3 at both the mRNA and protein levels while inhibited the expression of the anti- apoptotic gene Bcl-2. The expressions of p-Akt and p-Erk1/2 were decreased in HCT-116 cells after Apatinib treatment, but the total protein levels did not undergo obvious changes. CONCLUSION: Apatinib inhibits the proliferation and induces apoptosis of HCT-116 cells by suppressing the phosphorylation of Erk1/2 and Akt in the MAPK/Erk and PI3K/Akt signaling pathways.

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects.[Pubmed:28331317]

Int J Nanomedicine. 2017 Mar 10;12:1941-1958.

Apatinib is an oral tyrosine kinase inhibitor, which selectively targets vascular endothelial growth factor receptor 2 and has the potential to treat many tumors therapeutically. Cyclic arginylglycylaspartic acid (cRGD)- and polyethylene glycol (PEG)-modified liposomes (cRGD-Lipo-PEG) were constructed to act as a targeted delivery system for the delivery of Apatinib to the human colonic cancer cell line, HCT116. These cRGD-modified liposomes specifically recognized integrin alphavbeta3 and exhibited greater uptake efficiency with respect to delivering liposomes into HCT116 cells when compared to nontargeted liposomes (Lipo-PEG), as well as greater death of tumor cells and apoptosis. The mechanism by which cRGD-Lipo-PEG targets cells was elucidated further with competition assays. To determine the anticancer efficacy in vivo, nude mice were implanted with HCT116 xenografts and treated with Apatinib-loaded liposomes or free Apatinib intravenously or via intragastric administration. The active and passive targeting of cRGD-Lipo-PEG led to significant tumor treatment targeting ability, better inhibition of tumor growth, and less toxicity when compared with treatments using uncombined Apatinib. The results presented strongly support the case for cRGD-Lipo-PEG representing a targeted delivery system for Apatinib in the treatment of colonic cancer.

Apatinib treatment combined with chemotherapy for advanced epithelial ovarian cancer: a case report.[Pubmed:28352185]

Onco Targets Ther. 2017 Mar 13;10:1521-1525.

Apatinib is a novel oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has been proved by clinical trials to be effective and safe for patients with chemotherapy-refractory gastric cancer. To date, there is no study or case report on Apatinib treatment for patients with ovarian cancer. Here, we present the case of a 50-year-old Chinese woman with advanced ovarian cancer, who received Apatinib at a daily dose of 500 mg for 28 days per cycle after failure of fourth-line chemotherapy. Favorable oncologic outcome was achieved in this case after treatment with Apatinib. The patient's progression-free survival is now 11.3 months, and she is taking Apatinib and capecitabine as maintenance treatment. The common side effect of Apatinib was fatigue; however, the toxicity of Apatinib was controllable and tolerable. Thus, Apatinib may be an option for chemotherapy-refractory advanced epithelial ovarian cancer, but this still warrants further investigation.

Salvage treatment with apatinib for advanced non-small-cell lung cancer.[Pubmed:28367065]

Onco Targets Ther. 2017 Mar 23;10:1821-1825.

OBJECTIVE: No definitive chemotherapeutic regimen has been established in patients with non-small-cell lung cancer (NSCLC) who failed second- or third-line treatment. The aim of this study was to evaluate Apatinib, a VEGFR-2 inhibitor, in advanced NSCLC as salvage treatment. METHODS: We evaluated the efficacy and toxicity of Apatinib in patients with previously treated advanced NSCLC from 2014 to 2015 in Zhejiang Cancer Hospital. Survival analysis was performed by the Kaplan-Meier method. RESULTS: Forty-two patients were included in the present study. Four patients achieved partial response, and 22 achieved stable disease, representing a response rate of 9.5% and a disease control rate of 61.9%. Median progression-free survival and overall survival were 4.2 and 6.0 months, respectively. The toxicities associated with Apatinib were generally acceptable with a total grade 3/4 toxicity of 50%. CONCLUSION: Apatinib appears to have some activity against advanced NSCLC when utilized as salvage treatment.

Apatinib free base (YN968D1 free base) is an orally bioavailable tyrosine kinase inhibitor, which selectively targets VEGFR-2 (IC50=1 nM). Apatinib free base (YN968D1 free base) is an anti-angiogenic drug for the treatment of advanced or metastatic gastric cancer. Apatinib free base (YN968D1 free base) potently inhibits Ret, c-Kit and c-Src with IC50s of 13, 429 and 530 nM, respectively. It also inhibits cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ.

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