The Effects And Mechanism Of Combination Drugs On Prostate Cancer

Prostate cancer is one of the most common cancer,and is the sixth cause of male cancer worldwide.Prostate cancer incidence have increased in the most of countries,especially developed countries.Many factors that cause prostate cancer include diet,lifestyle,prostate infection and DNA.Development of new combination drugs based on growth signaling pathway on prostate cancer cell had become a hot research area for treatment of advanced prostate cancer around the world.The purpose of this research project is to provide different drug combinations according to the survival and growth signaling pathway on prostate cancer cell,and improve therapeutic effect as well as decrease drugs side effects.The project may provide important reference data and science evidence in clinical research for targeted combination drugs in the future from a different angle.Cazazitaxel,a new paclitaxel chemotherapy drugs,has side effect and drug resistance affect therapeutic effect of cabazitaxel.Enzalutamide can inhibit AR signaling pathway,which can increase effect of cabazitaxel.Previous experiment result in our research group showed that atorvastatin can inhibit the growth of prostate tumor through inhibition of Akt and Erk signaling pathway,and improve therapeutic effect in advanced prostate cancer.Flavonoids can prevent PSA produced in prostate cancer cell line and induce cell apoptosis,and atorvastatin combined flavonoids may produce the synergistic effect on the growth of prostate cancer cell.Meanwhile,statins can induce some patients with muscle side effect and P450 3A4(CYP3A4)is the major risk substance,but flavonoids can inhibit CYP3A4 activity in human liver microsomes,so flavonoids in combination with atorvastatin not only increase therapeutic effect but also reduce side effect.Aspirin has inhibition effect on tumor because it can reduce the expression level of COX-2 in patients.Lansoprazole can inhibit the expression level of NF-kB.Atorvastatin,aspirin combined with lansoprazole may strongly increase effect of anti-prostate cancer.Lansoprazole can decrease injury to gastrointestinal tract that aspirin result in,because lansoprazole is medicine for curing gastric ulcer.The present study explored the effect of cabazitaxel combined enzalutamide or alone on prostate cancer cell PC-3 and LNCaP,and the effect of atorvastatin combined naringin or alone on PC-3 and LNCaP,and the effect of atorvastatin,aspirin combined lansoprazole or alone on VCaP.The study used MTT assay to determine cabazitaxel combined enzalutamide or alone on the growth inhibition of PC-3 and LNCaP.Paper used MTT assay to determine atorvastatin and naringin alone on the growth inhibition of PC-3 and LNCa P,and it used MTT assay,CCK-8 assay and Trypan Blue assay to determine atorvastatin combined naringin under low toxic concentration on the growth inhibition of PC-3 and LNCaP,calculating CI value.The study confirmed the best combination of atorvastatin and naringin under low toxic concentration,the study used propidium iodide staining combined with morphological analysis to evaluate single drug and combination drugs on the apoptosis of PC-3 and LNCaP,and it used scratch experiment to evaluate single drug and combination drugs on the migration ability of PC-3 and LNCa P,and it applied matrigel invasion experiment to assess single drug and combination drugs on the invasion ability of PC-3 and LNCaP,then it used western blot method to determine the expression level of AR,p-STAT3,survivin,Bax,Bcl-2 and p-Akt of PC-3 and LNCaP treated single drug and combination drugs,and at last it applied the SCID mice xenograft to assess the growth of prostate tumor treated single drug and combination drugs.Paper used Trypan Blue assay to determine atorvastatin,aspirin combined lansoprazole on the growth inhibition of VCaP,and used propidium iodide staining combined with morphological analysis to evaluate single drug and combination drugs on the apoptosis of VCaP,and used luciferase assay to determine the expression level of NF-kB of VCaP treated single drug and combination drugs.The present study demonstrated cabazitaxel combined enzalutamide or alone had inhibition effect on the growth of PC-3 and LNCaP,and the combination had stronger inhibition.The study also demonstrated atorvastatin combined naringin or alone had inhibition effect on the growth of PC-3 and LNCaP,and the combination had stronger inhibition,in addition,two drugs had synergism effect on PC-3 and LNCaP,and two drugs had inhibition effect on migration and invasion of prostate cancer cell,at the same time,the combination drugs had stronger inhibition,what's more,combination drugs had more effectiveness to induce apoptosis than single drug.At the molecular level,the Bax expression level of atorvastatin combined naringin group was higher than two single groups,and the Bcl-2 expression level of combination drugs was lower than two single groups in PC-3 cell,and both single drug and combination drugs can inhibit the expression level of pAkt and p-STAT3,and atorvastatin combined naringin had more inhibition effect on the expression level of AR on LNCaP according to the result of AR determination and analysis.Atorvastatin combined naringin or alone had inhibition growth on prostate tumor,and it had significant correlation between two single drugs and combination drugs,and combination group had more inhibition effect.The study demonstrated atorvastatin,aspirin combined lansoprazole or alone had inhibition effect on VCaP,and folfoxiri had stonger inhibition and also had more effectiveness to induce apoptosis,and folfoxiri had more inhibition effect on the level of NF-kB than two drugs combination and single drugs.To sum up,the study provided three combination therapies,including cabazitaxel combined with enzalutamide,atorvastatin combined with naringin,and the combination of atorvastatin,aspirin and lansoprazole.The three combination therapies can increase drug potency not only,but also reduce side effect of drugs under low drug concentration.The study provided the theoretical basis and clinical research basis to cure prostate cancer patient using therapeutic combinations.