WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer
Authors: Zhao Hong , Li Rong , Wang Xiaoyan , Lu Xin , Hu Min , Zhang Jinbin , Zhao Xia , Song Xiaoqin , Liu Yangyang 
Published: April 2020

Abstract

Objective
To 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.
Methods
Conventional 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 the role of Apatinb was 50.66 ± 4.96umol/L(48 h). (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 invasion and migration of the cells decreased after the nab-P and AP treatment(P < 0.01). (4) nab-P combined with AP can increased their antitumor effect, according to Compusyn software, CL < 1. (5) After combined with AP, when nab-P were reduced dose in proper quantity, there were no obvious different in drug effect. (6) Reduced nab-P can increased nude mice’s quality of life.
Conclusion
Paclitaxel (albumin binding type), a chemotherapeutic agent, can play an anti-tumor role in drug-resistant ovarian cancer, but it can also reduce the tumor load and increase the expression of tumor vascular endothelial growth factor. When combined with Apatinib, the target drug of anti vascular endothelial growth factor, the two drugs have synergistic effect, which can improve the effect of single drug. In addition, when combined with Apatinib, the dosage of Paclitaxel (albumin binding type) can be appropriately reduced under the standard of recommended dosage to reduce the toxicity of chemotherapy drugs, without affecting the anti-tumor effect.