The Anti-tumor Activity Of Otobain Derivatives

Cancer is a threat to public health worldwide and ranks the second diseases leading to death.In the next few years or decades,cancer is expected to be the first common diseases of death worldwide.The detection methods and treatments of tumor progressed in recent years so that the survival rate of tumor patients improved greatly.Clinical patients benefit from the increased number of chemotherapeutic drugs and improved chemotherapeutic regimens.However,the benefits of the treatments are gradually weakened due to quick development of resistance by tumors,uncontrolled side effects of chemotherapeutic agents and drug interactions.These limit the clinical use of many drugs and result in the failure of treatment.Therefore,it is urgent to discover new chemotherapeutic drugs with higher cytotoxicity to tumor cells and lower side effects to human bodies.Based on cell phenotypic screening,we discovered a candidate compound L45 from a series of novel 1,2-trans-otobain-podophyllotoxin hybrids with potent ability to inhibit the growth of tumors.Compound L45 inhibited cell viability in a dose-dependent manner in cells from five different cancer types in vitro,including leukemia,stomach cancer,breast cancer,colorectal cancer and lung cancer,with IC50 values ranging from 1.06 ?M to 4.16 ?M.Compound L45 effectively inhibited colony formation of the non-small cell lung cancer A549 cells.We further found that L45 inhibited the polymerization of microtubule and induced A549 cell cycle arrest in M phase in time-and dose-dependent manners,but it could not markedly trigger cell apoptosis.Moreover,L45 significantly suppressed tumor volume(P<0.01)in a subcutaneous xenograft mouse model without showing impact on mouse body weight.In order to find more effective chemotherapeutic drugs,we further identified another candidate compound C5-1 from a series of novel compounds including two chiral isomers of L45,several 1,2-cis-otobain-podophyllotoxin hybrids and chiral isomers of C5.Our results showed that compound C5-1 inhibited cell viability in four different cancer cell lines in vitro,with IC50 values ranging from 0.43?M to 0.87 ?M.It effectively inhibited the colony formation of A549 cells at the concentration of 0.1?M.It induced cell cycle arrest in M phase and triggered cell apoptosis in time-and dose-dependent manners in A549 cells.C5-1 could also suppressed cell migration at a low concentration.However,it hardly suppressed the growth of A549 in vivo.In summary,L45,an otobain derivative with trans configuration,could inhibit the growth of A549 in vitro and in vivo by inducing cell cycle arrest in M phase and inhibing the polymerization of microtubule.C5-1,an otobain derivative with cis configuration,suppressed the growth and metastasis of A549 in vitro.Our findings provide foundermental evidences for further development of otobain derivatives.