Action Mechanism Of The Anticancer And Radiosensitivity Of Ruthenium Imidazole Complexes And Antipsychotic Drugs

The accessible oxidation states?II,III and IV?,wide coordination numbers,and thermodynamic and kinetic characteristics similar to platinum complexes make ruthenium?Ru?complexes facilitative for the coordination,organometallic chemistry,catalysis,photochemistry,and biochemistry.In particular,its promising antitumor and anti-metastatic activities flourish anticancer drugs field.Cancer and its aggressive therapies maybe result in many side effects.The most common side effects include bone loss,fatigue,pain,and psychosis.In this study,we designed and synthesized a serious of imidazole-based Ru complexes,and investigated their anticancer effects.To deal with cancer treatment,we also investigated the anticancer effects of antipsychotic drugs.1.Radioresistance has become the major factor for radiotherapy failure in clinical,which arouses the development of radiosensitizer in recent years.In the present study,a series of selenium?Se?-containing ruthenium?Ru?complexes?Se-Ru?,namely,[Ru?bim?₂?bpyse?]?Cl O₄?₂?Ru Se-1?,[Ru?bpy?₂?bpyse?]?Cl O₄?₂?Ru Se-2?,and[Ru?phen?₂?bpyse?]?Cl O₄?₂?Ru Se-3??bim=2,2-biiminazole;bpy=2,2-bipyridine;phen=1,10-phenanthroline;bpyse=5-?3,4-diaminophenyl?-2,1,3-benzoselenadiazolein?,have been rationally designed,and synthesized,and the underlying mechanisms accounting for their anticancer action and radiosensitization effects on clinically used X-ray were also elucidated.The results showed that,the complexes exhibited higher selectivity between human cancer and normal cells,and could sensitize human cervical cancer cells with sensitivity enhancement ratio at 3.0 through induction of cell apoptosis and G2/M cell cycle arrest.Moreover,the complexes effectively inhibited the expression of Trx R,and thus enhanced the intracellular reactive oxygen species?ROS?generation.Meanwhile,mitochondria fragmentation was also observed in cells exposed to Se-Ru complexes,as regulated by change in expression levels of Bcl-2 family proteins.Furthermore,ROS overproduction induced by combined treatment of the complexes and X-ray activated the downstream signaling,including p53,AKT and MAPKs pathways,to achieve synergistic anticancer effect.Taken together,this study demonstrates a strategy for rational design of the next-generation radiosensitizers based on Se-containing metal complexes.2.Metastasis is the major cause for mortality,which can attack adjacent cells and spread cancer cells from one organ to other organ without direct relationship.Six Ru complexes,namely,[Ru?bim?₂?pimp?]?Cl O₄?₂?1?,[Ru?dppz?₂?pimp?]?Cl O₄?₂?2?,[Ru?bim?₂?dppz?]?Cl O₄?₂?3?,[Ru?dppz?₂?bim?]?Cl O₄?₂?4?,[Ru?pimp?₂?dppz?]?Cl O₄?₂?5?,and[Ru?pimp?₂?bim?]?Cl O₄?₂?6??dppz=dipyrido[3,2-a:2',3'-c]phenazine,andpimp=2-?4-methoxyphenyl?-1H-imidazo[4,5-f][1,10]phenanthroline?was designed,synthesized,and characterized in this study.We investigated the antiproliferative effects of six Ru complexes in MCF-7,MDA-MB-231,A375,A549,and He La human cancer cells and HK-2 human normal cells.Complexes 3 and 4 containing bmi and dppz ligands possessed widely potent anticancer activities in all cancer cell lines,while without compromising for HK-2 cells.In addition,the complex 4 was more efficient to inhibit invasion and migration in MDA-MB-231 cells than complex 3 at low dose.Further investigation revealed that the complex 4 activated DNA damage-mediated activation of p53 and induced extrinsic death receptor and intrinsic mitochondrial apoptotic associated with AKT and MAPKs signaling pathways in invasive MDA-MB-231 cells.These results suggested that the novel 4 complex could be an effective antimetastasis agent for breast cancer treatment.3.Psychosis,an abnormal condition of the mind,is a common symptom in various kinds of cancer patients.In the study,we investigated the effects of 17 antipsychotic drugs in different cancer cells,namely amisulpride,aripiprazole,chlorpromazine,clozapine,flupenthixol,flupentixol HCl,haloperidol,loxapine succinate,olanzapine,paliperidone,pimozide,quetiapine fumarate,risperidone,trazodone HCl,trifluoperazine,thioridazine and ziprasidone hydrochloride monohydrate,to determine whether it could enhance or inhibit the cancer cells grow and curcumin was a comparison.All the antipsychotic drugs did not enhance cancer cells growth in 10 and 20?M.Moreover,some of them have significant inhibited the growth of different cancer cell lines.In addition,flupenthixol,chlorpromazine,and clozapine conspicuously inhibited the TNF induced NF-?B activation in human chronic myeloid leukemia cells.We further demonstrated trifluoperazine suppressed the expression of anti-apoptotic proteins?Bcl-2,c-IAP1/2,XIAP,Bcl-X_L,and survivin?,proliferative proteins?cyclin D1/COX-2?,tumor invasive proteins?MMP-9?,and angiogenesis?VEGF?.Trifluoperazine also induced the cleavage of caspase 9/8/3,and PARP.These results suggested that antipsychotic drug trifluoperazine was a potent anticancer drug in human chronic myeloid leukemia cells.