A phase II study of apatinib in patients with recurrent epithelial ovarian cancer

Ming-ming, Miao; Deng, Guanming; Luo, Sujuan; Zhang, Jiajia; Chen, Le; Yang, Jun; He, Jie; Li, Junjun; Yao, Jing; Tan, Shanmei; Tang, Jie

doi:10.1016/j.ygyno.2017.12.013

Cited by 78 publications

(95 citation statements)

References 28 publications

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“…Many research have shown that AP has showed strong tumor inhibition and tolerance in non-small cell lung cancer, gastric cancer, breast cancer and other malignant solid tumors [15][16][17], in OC patients, many achievements have also been made, in a phase II clinical study of recurrent epithelial ovarian cancer, the objective response rate (hereinafter referred to as ORR) of patients was 41.4%, and PFS was 14.5 months [18], in 2018, an article published in Lancet Oncol on the treatment of advanced ovarian cancer patients with AP and Etoposide showed that up to 54% of patients achieved remission [19], and in the same year, Jiuhuan found that the combination of AP and radiation paclitaxel can significantly inhibit tumor growth [20]. Therefore, we propose whether AP combined with nab-P can improve the therapeutic effect on platinum-relapsed patients.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

Zhao

Wang

et al. 2020

Preprint

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ObjectiveTo assess the antitumor effects and side reactions of different dosages of Paclitaxel (albumin binding) combined with Apatinib in drug-resistant ovarian cancer cell line and xenotransplantation tumor model. MethodsConventional cell experiments were used to evaluate the effects of Apatinib and Paclitaxel (albumin binding), SKOV-3/DDP were selected as research object and divided into 3 groups for study, a): control group, no drug intervention; b): nab-P group, Paclitaxel (albumin binding type) 40 µmol/l; c): Apatinib group, Apatinib 50 µmol/l. The IC-50 value of the drug was detected by MTT test, apoptosis related protein(Bax, bcl-2), vascular related protein(p-VEGFR-2), invasion related protein(MMP-2) expression were detected by Western blot and Cellular immunofluorescence, the invasion and migration ability of tumor cells were detected by Transwell and Cell scratch test. Based on these dates, establishing different dosages of Paclitaxel (albumin binding type) combined with Apatinib, a): Control group, no drug intervention; b): Group-1, Paclitaxel (albumin binding type) 5 µmol/l + Apatinib 10 µmol/l, c): Group-2, Paclitaxel (albumin binding type) 4.5 µmol/l + Apatinib 10 µmol/l, d): Group-3, Paclitaxel (albumin binding type)4 µmol/l + Apatinib 10 µmol/l, the index of combined use was analyzed by Compusyn software, Western blot, Immunofluescence, Transwell, Cell scratch test also were chose to change of inhibition effect. On the other hand, we used xenograft tumor model to verify the results in vivo. BALB/c female nude mice were randomly divided into 4 groups, a): Control group, no drug intervention; b): Paclitaxel (albumin binding type) 20 mg/kg + Apatinib 150 mg/kg, c): Paclitaxel (albumin binding type) 18 mg/kg + Apatinib 150 mg/kg, d): Paclitaxel (albumin binding type) 16 mg/kg + Apatinib 150 mg/kg. The tumor growth curve was analyzed during the test. The apoptosis related protein (Bax, bcl-2), angiogenesis related protein (CD31, p-VEGFR-2) and invasion related protein(MMP-2) were analyzed by Western blot, Immunofluescence and Immunohistochemistry to analysis the effect of antitumor and side reactions Result (1) The IC-50 value of SKOV-3/DDP to paclitaxel (albumin binding type) was 45.53 ± 4.06 µmol/l, while

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

Zhao

Wang

et al. 2020

Preprint

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“…In OC, many achievements have also been made. In a phase II clinical study of recurrent epithelial ovarian cancer, the objective response rate (ORR) of patients was 41.4%, and PFS was 14.5 months [18] . In 2018, an article published in Lancet Oncol on the treatment of advanced ovarian cancer patients with AP and Etoposide showed that up to 54% of patients achieved remission [19] , and in the same year, Jiuhuan [20] found that the combination of AP and standard paclitaxel can signi cantly inhibit tumor growth.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Role of Apatinib Combined with Paclitaxel (aluminum binding type) in Platinum-resistant Ovarian Cancer

Zhao

Wang

et al. 2020

Preprint

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Objective: To assess the anti-tumor activity and side effects of different dosages of paclitaxel (albumin binding type) (hereinafter referred to as nab-P) combined with Apatinib (hereinafter referred to as AP) in platinum-resistant ovarian cancer cell line and xenograft models.Methods: SKOV-3/DDP cell line was selected as the research object in cytology experiment. Firstly, we divided it into three groups for experiments to explore the individual effects of nab-P and AP. a): Control group, blank control, no drug intervention; b): nab-P group, nab-P 40μmol/l; c): AP group, AP 50μmol/l (Drug doses were IC-50 values that detected by MTT assay). Apoptosis related protein(Bax, bcl-2), vascular related protein(p-VEGFR-2), invasion related protein(MMP-2) expression were detected by Western blot and Cellular immunofluorescence, the invasion ability of tumor cells were detected by Transwell and Cell scratch test. Based on these dates, secondly, establishing different doses of nab-P combined with Ap to explore the curative effect of combination therapy. a): Control group, blank control, no drug intervention; b): Group-1, nab-P 5μmol/l + AP 10μmol/l, c): Group-2, nab-P 4.5μmol/l + AP 10μmol/l, d): Group-3, nab-P 4μmol/l + AP 10μmol/l, e): nab-P group, nab-P 5μmol/l, f): AP group, AP 10μmol/l (MTT assay). The combination index was analyzed by Compusyn software, Western blot, Immunofluescence, Transwell and Cell scratch test also were also chose to observe of inhibition effect. Thirdly, we used xenograft models to verify the results of cytological experiments. Tumor-forming BALB/c female nude mice were randomly divided into 4 groups, a): Control group, no drug intervention, only saline injection, b): nab-P 20mg/kg + AP 150mg/kg , c): nab-P 18mg/kg + AP 150mg/kg, d): nab-P 16mg/kg + AP 150mg/kg(The doses were guided by the pharmaceutical manufacturers). The tumor growth curve was analyzed during the experiment. And the apoptosis related protein (Bax, bcl-2), angiogenesis related protein (CD31, p-VEGFR-2) and invasion related protein(MMP-2) were observed by Western blot, Immunofluescence and Immunohistochemistry to analysis the ant-tumor effects. The quality of life in nude mice were observed to analysed the drug-induced side effects.Result: In the separate medication section, (1) The IC-50 value of nab-P was 45.53±4.06 μmol/l, while the AP was 50.66±4.96 umol/L (48h). (2) The expressions of bcl-2 (nab-P group, AP group), p-VEGFR-2 (AP group), MMP-2(nab-P group, AP group) were higher than Control group, while Bax(nab-P group, AP group) lower (P<0.01). (3) The cell invasive ability was decreased after the nab-P and AP intervation (P<0.01). In the combination medication section, (1) Compusyn showed the Combination index (Cl) were all below 1 (Cl<1), that means nab-P and AP are synergism. (2) The combination IC-50 value was nab-P 5.28 μmol/l+AP 10.56 μmol/l (48h). (3) In the detection of related protein expression, the combination of drugs can improve the anti-tumor effect, otherwise, after combined with AP, when nab-P were reduced dose in proper quantity, there were no obvious different in drug effect. (4) After reducing the doses of nab-P, the average food intake of nude mice increased from 4.50 g±0.17 to 5.55 g±0.13, and the one-hour activity increased from 6.11min ±0.16 to 6.34 min ±0.13.Conclusion: nab-P, a chemotherapeutic agent, can play an anti-tumor role in platinum-resistant ovarian cancer, but it can cause adverse effects that increase with dose. When combined with AP, the two drugs have synergistic effect, which can improve the anti-tumor effects of single drug. In addition, when combined with AP, the doses of nab-P can be appropriately reduced under the standard of recommended to reduce the toxicity of chemotherapy drugs, without affecting the anti-tumor effect.

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“…Sunitinib is a multi-targeting agent directed against VEGFR-1, -2 and -3, platelet-derived growth factor receptor (PDGFR), c-Kit, FMS-like tyrosine kinase-3 and RET, and has been FDA approved for the treatment of renal cell cancer and gastrointestinal stromal tumors [32]. Recent clinical trials have shown that apatinib may benefit recurrent, platinum-resistant epithelial ovarian cancer patients with an acceptable safety profile [17]. In addition, it has been found that apatinib combined with oral etoposide shows a promising efficacy and manageable toxicity in platinumresistant and platinum-refractory ovarian cancers [18].…”

Section: Discussionmentioning

confidence: 99%

“…Some case reports have indicated that apatinib may be an option for patients with chemotherapy-refractory advanced epithelial ovarian cancer [15,16]. A phase II study has shown that apatinib may be a feasible treatment option for recurrent, platinum-resistant epithelial ovarian cancer [17], and another recent phase II prospective study suggests that apatinib combined with etoposide may show promising effects with manageable toxicities in platinum-refractory ovarian cancer [18]. SRY-related high-mobility-group box 5 (SOX5) is a member of the SOX family of proteins and acts as a transcription factor involved in the regulation of embryonic development and cell fate determination [19].…”

Section: Introductionmentioning

confidence: 99%

Apatinib inhibits glycolysis by suppressing the VEGFR2/AKT1/SOX5/GLUT4 signaling pathway in ovarian cancer cells

Chen

Cheng

et al. 2019

Cell Oncol.

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Background Apatinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), and has shown encouraging therapeutic effects in various malignant tumors. As yet, however, the role of apatinib in ovarian cancer has remained unknown. Here, we sought to elucidate the role of apatinib in the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as in glucose metabolism in these cells. Methods The effects of apatinib on ovarian cancer cell viability and proliferation were assessed using Cell Counting Kit-8 (CCK-8) and colony formation assays, respectively. The expression of VEGFR2/AKT1/SOX5/GLUT4 pathway proteins was assessed using Western blotting, and glucose uptake and lactate production assays were used to detect glycolysis in ovarian cancer cells. SOX5 was exogenously over-expressed and silenced in ovarian cancer cells using expression vector and shRNA-based methods, respectively. RNA expression analyses were performed using RNA-seq and gene-chip-based methods. GLUT4 promoter activity was assessed using a dual-luciferase reporter assay. The expression of p-VEGFR2 (Tyr1175), p-AKT1 (Ser473), p-GSK3β (Ser9), SOX5 and GLUT4 in xenograft tissues was assessed using immunohistochemistry (IHC). Results We found that apatinib inhibited the in vitro and in vivo viability and proliferation in Hey and OVCA433 ovarian cancer cells in a dose-dependent and time-dependent manner. We also found that apatinib effectively suppressed glucose uptake and lactate production by blocking the expression of GLUT4 in these cells. In addition, we found that SOX5 predominantly rescued the inhibitory effect of apatinib on GLUT4 expression by activating its promoter. Finally, we found that apatinib regulated the expression of SOX5 by suppressing the VEGFR2/AKT1/GSK3β signaling pathway. Conclusions From our results, we conclude that apatinib suppresses the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as glycolysis by inhibiting the VEGFR2/AKT1/GSK3β/SOX5/GLUT4 signaling pathway. Apatinib may serve as a promising drug for the treatment of ovarian cancer.

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A phase II study of apatinib in patients with recurrent epithelial ovarian cancer

Cited by 78 publications

References 28 publications

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

WITHDRAWN: The Role of Apatinib Combined with Paclitaxel (aluminum binding type) in Platinum-resistant Ovarian Cancer

Apatinib inhibits glycolysis by suppressing the VEGFR2/AKT1/SOX5/GLUT4 signaling pathway in ovarian cancer cells

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