Synergistic Antitumor Effects Of Sorafenib And Lapatinib In PC-3 Cells

Prostate cancer is the sixth most common cancer in China which has increased the trend of incidence rate.Precision therapy of prostate cancer is the greatest challenge to the health care and scientific research.The androgen independence and metastasis of prostate cancer at the late stage have made various treatments ineffective.Single drug chemotherapy has many problems,such as,high doses,toxicity and drug resistance,so that development of multi-target small molecule drugs has become the focus of cancer treatment.Currently,most of the targeted agents for cancer treatment are tyrosine kinase inhibitors（TKIs）.So far,thirteen TKIs have been approved by the FDA（United States）for the targeted therapy of breast cancer,non-small cell lung cancer,chronic myeloid leukemia,renal cell carcinoma etc.Sorafenib and lapatininb are the two TKIs that have been approved for the treatment of several cancers.In 2005,the FDA and the European Union approved sorafenib for the treatment of advanced liver cancer and renal cell carcinoma.In recent years,it was also approved to treat the thyroid cancer.Lapatinib is the second TKI for targeted therapy of breast cancer after trastuzumab,and was approved by FDA in 2007 in combination with capecitabine for the treatment of advanced or metastatic breast cancer which has high expression level of EGFR/ErbB2.However,the antitumor effects of the combination of sorafenib and lapatinib in prostate cancer cells have not been reported yet.This thesis studied the antitumor effects of the combination of sorafenib and lapatinib in the androgen independent prostate cancer PC-3 cells,and also tried to identify its mechanism.The aim of this study is to explore a drug combination with lower concentration,lower side effects and better synergistic effects.This study will provide new clues and experimental data for the targeted therapy of prostate cancer,especially castration-resistant prostate cancer（CRPC）.MTT assay showed that sorafenib and lapatinib had synergistic inhibitory effect on the survival of PC-3 cells.Sorafenib and/or lapatinib also had significant inhibitory effects on the clonogenecity,spheroid formation and migration of PC-3 cells,and the combination was more effective than the single drug.Western blot and fluorescence confocal microscopy results showed that sorafenib and lapatinib had no significant effect on cell apoptosis,but significantly affected autophagy.Lysosomal inhibitors NH₄Cl,E64d,PepstainA in combination with sorafenib,lapatinib had no significant effect on the autophagy marker LC3B-II compared with the inhibitors alone,suggesting that the combination of sorafenib and lapatinib inhibited the fusion of autophagosome and lysosome.Further studies showed that the combination of sorafenib and lapatinib significantly reduced the phosphorylation level of Akt,but had no effects on the phosphorylation of STAT-3.In conclusion,this thesis found for the first time that sorafenib and lapatinib had synergistically inhibitory effects on the survival,proliferation,spheroid formation and migration of PC-3 cells.However,sorafenib and lapatinib affected the autophagy of PC-3cells synergistically,by blocking the fusion of autophagosome and lysosome.PI3K/Akt signaling pathway may play an important role in mediating the synergistic effect of sorafenib and lapatinib.These results suggested that sorafenib and lapatinib have synergistic antitumor effects.Therefore,this study demonstrates the potential of sorafenib and lapatinin in combination in the clinical treatment of prostate cancer,and also provides a new strategy for the targeted therapy of the castration-resistant prostate cancer.