WZ-8, A New PARP Inhibitor, Exhibits Potent Antitumor Effects In Vitro And In Vivo

Objects:WZ-8, a new PARP inhibitor, is a kind of compound with structural modification of INBA, this study evaluated the inhibitory effect of WZ-8on various sources of human tumor cell proliferation, and studied the experimental therapeutic effect of WZ-8on human cell xenografted nude mice model.Methods:1) Determination of the proliferation inhibition of tumor cells from various sources treated with WZ-8alone in vitro by SRB assay.2) Determination of the proliferation inhibition of the proliferation inhibition of tumor cells from various sources treated with WZ-8combined with anti cancer drugs in vitro by SRB assay.3) Inhibitory effect of WZ-8alone in MDA-MB-231xenografted nude mice.4) Inhibitory effect of WZ-8combined with Gemcitabine in HCT116xenografted nude mice.5) Inhibitory effect of WZ-8or BSI-201combined with Gemcitabine in HCT116xenografted nude mice.6) Inhibitory effect of WZ-8combined with cisplatin in HCT116xenografted nude mice.Results:1) IC50value of WZ-8for all kinds of human tumor cell lines was0.21-1.17μ g/ml, which was stronger than the positive control INBA in inhibitory effect on tumor cells, and showed favorable antitumor activity.2) WZ-8combined with cisplatin showed superimposed effect on the anti-proliferation effect of A431, PC3, SGC-7901, MCF-7, and showed antagonistic effect on the anti-proliferation effect of MDA-MB-231, and showed antagonistic effect or superimposed effect on the anti-proliferation effect of KB, and showed no synergetic effect on HCT116, A2780,786-O, A549, MDA-MB-436cells. Meanwhile, WZ-8combined with gemcitabine or TPT or VP-16showed antagonistic effect on the anti-proliferation effect of on MCF-7, MDA-MB-231cells.3) In the anti-tumor effect of WZ-8alone in MDA-MB-231xenografted nude mice, tumor volume of Taxol l0mg/kg, WZ-825mg/kg, WZ-812.5mg/kg and WZ-86.25mg/kg groups after21days were1209±160mm3,1268±188mm3,1465±283mm3and1501±336mm3, with relative tumor volume6.9±0.8,9.1±1,9.8±0.9and10.1±2, and T/C values were61.8%,82.3%,87.8%and91.3%, corresponding to the tumor weight was0.66±0.08g,0.90±0.19g,0.98±0.25g and1.01±0.25g, with the inhibition rates25.5%,13.9%,5.8%and3.3%, respectively.4) In the anti-tumor effect of WZ-8combined with gemcitabine in HCT116xenografted nude mice, tumor volume of gemcitabine100mg/kg,50mg/kg,25mg/kg, WZ-825mg/kg, WZ-825mg/kg plus gemcitabine100mg/kg, WZ-825mg/kg plus gemcitabine50mg/kg, and WZ-825mg/kg plus gemcitabine25mg/kg group after21days were1420±443mm3,1480±199mm3,1392±417mm3,2255±307mm3,703±132mm3,1396±373mm3and3129mm3, with relative tumor volume5±1.2,6.2±1.5,6.8±3,8.7±2.9,5.8±3.4,5.6±1.7and3.4, and T/C values39.7%,49.1%,54.2%,68.7%,45.9%,44.7%and26.8%, corresponding to the tumor weight was1.22±0.27g,1.49±0.14g,1.49±0.28g,2.15±0.44g,1.04±0.19g,1.30±0.32g and2.52g, with the inhibition rates54.1%,44.3%,44%,19.4%,60.8%,51.4%and5.5%.5) In the anti-tumor effect of WZ-8or BSI-201combined with gemcitabine in HCT116xenografted nude mice, tumor volume of WZ-825mg/kg, WZ-812.5mg/kg, gemcitabine130mg/kg, WZ-825mg/kg plus gemcitabine130mg/kg, WZ-812.5mg/kg plus gemcitabine130mg/kg group after27days were1679±217mm3,1725±448mm3,799±69mm3,895±137mm3and687±138mm3(in solvent control group, tumor volume was2409±236mm3), with relative tumor volume of10.9±0.8,10.9± 1.5,4.9±0.4,5.4±0.6and4.8±1, and T/C values71.2%,71.1%,32.3%,35.1and31%. The tumor volume of BSI-20190mg/kg, gemcitabine130mg/kg,BSI-20190mg/kg plus gemcitabine130mg/kg after27days were2114±239mm3,799±69mm3and913±136mm3(in solvent control group, tumor volume was2409±236mm3), with relative tumor volume14±2.5,5±0.4and6±1, and T/C value91.1%,32.3%and39.4%, respectively. The mice were sacrificed and the tumor weight was measured, the tumor weight of WZ-825mg/kg, WZ-812.5mg/kg, gemcitabine130mg/kg, WZ-825mg/kg plus gemcitabine130mg/kg and WZ-812.5mg/kg plus gemcitabine130mg/kg were1.46±0.15g,1.41±0.47g,0.69±0.07g,0.72±0.12g and0.79±0.04g (in solvent control group tumor weight was1.04±0.12g), with inhibition rates of37.4%,39.5%,70.4%,69%and66.2%. The tumor weight ofBSI-20190mg/kg, gemcitabine130mg/kg and BSI-20190mg/kg plus gemcitabine130mg/kg group were2.05±0.35g,0.69±0.07g and0.76±0.12g (in solvent control group, the tumor weight was1.04±0.12g), with inhibition rates11.9%,70.4%and67.3%,respectively.Conclusions:WZ-8and INBA showed different proliferation inhibitory activity in10different strains of tumor cell. The IC50value of WZ-8was0.2-1.2μg/ml, which was better than INBA (IC50:20-60μg/ml). WZ-8combined with gemcitabine or cisplatin could inhibit the tumor volume of HCT116human colon cancer xenograft in nude mice. WZ-8alone or in combination with anti tumor drugs exhibited antitumor activity in vitro or in vivo showed that as a specific PARP inhibitor, WZ-8was expected to develop into a class of antitumor drug. And this study provided theoretical and experimental basis for the "clinical application and research, and the development of PARP inhibitors.