Studies On Synthesis And Antitumor Activity Of Novel Transition Metal Complexes

Metal-based anti-cancer drugs were developed many years ago. In recent years, the study hasshown that a number of the metal-based drugs, including organic copper-, zinc-, and gold-basedcomplexes, are capable of inhibiting the tumor cell proteasome, thereby inducing cancer celldeath. Ubiquitin proteasome pathway is the major proteolytic mechanism which plays a criticalrole in the degradation of the proteins. The20S proteasome, the main component of the UP-S, isa high molecular weight protease complex with a proteolytic core containing subunits includingβ1, β2and β5, which are responsible for its caspase-like, trypsin-like and chymotrypsin-like(CT-like) activities, respectively. It is well established that inhibition of the β5proteasomalsubunit, and therefore its CT-like activity, is primarily associated with apoptosis induction intumor cells. The ubiquitin proteasome pathway has therefore been extensively studied as a novelmolecular target for the development of novel drugs in an attempt to restore protein homeostasisas the ultimate therapeutic strategy.In the current study, several transition metal complexes are synthesised which may havepotential anticancer activities. The abilities to inhibit cell proliferation, chymotrypsin-likeactivity of proteasome and induce apoptosis are investigated in human cancer cells. Themechanism of these complexes to inhibit proteasome and induce apoptosis in cancer cells arestudied, and make sure the antitumor target is proteasome.The details of the contents are as follows,(1) Two types of copper complexes, dinuclear complexes and ternary complexes aresynthesized, to investigate whether a certain structure could easily carry copper into cancer cellsand consequently inhibit tumor proteasome activity and induce apoptosis. The abilities of theligands and copper complexes to inhibit cell proliferation in human prostate cancer PC3cells andchymotrypsin-like activity of purified20S proteasome are investigated firstly. Furthermore, theproteasome-inhibitory and apoptosis–inducing activities of these compounds in the PC3prostatecancer cells are studied. Finally, compare the effects of proteasome inhibition and apoptosisinduction in breast cancer MDA MB231cells and normal MCF10A cells with ternarycomplexes. The new findings suggest that (i) copper binding with1,10-phenanthroline as the third ligand could promote tumor cells to uptake copper, resulting in potent proteasomeinhibition and apoptosis induction in cancer cells, and (ii) breast cancer MDA MB231cells aremore sensitive to the novel candidates ternary complexes than non-tumorigenic cells, suggestingtumor-selective targeting.(2) Novel metal-containing complexes are synthesized by using indole-3-butyric acid (L1)and indole-3-propionic acid (L2) respectively, as ligands. These Cd complexes are potentinhibitors of the proteasome and inducers of apoptosis, effects which appear to be specific totumor cells. Then use proteasome activity, MTT assay and western blot to compare the ability ofthe similar metal complexes containing copper (Cu), zinc (Zn) or Cd to inhibit breast cancer cellproliferation using the estrogen receptor (ER)-positive MCF7and ER-negative MDA MB231breast cancer cell lines. Of the compounds tested, the Cd-containing versions appear to be themost potent inhibitors of cellular proteasome CT-like activity and effective inducers of apoptosisin breast cancer cells, but not in non-tumorigenic breast epithelial MCF10A cells. Additionally,these newly synthesized Cd compounds are superior in potency and cancer selectivity to theDSF-Cd mixture.(3) The ligands (Cefepime) and the mixture of the transition metal with the ligands havebeen prepared. The activity of proteasome inhibition and the apoptosis induction in human breastcancer MDA MB231cells by the mixture are studied. Firstly, compare the ability of thedifferent metal complexes to inhibit breast cancer cell proliferation using the estrogen receptorER-negative MDA MB231breast cancer cell lines. All the results showed that only manganesemixture could inhibit cell proliferation in human breast cancer MDA MB231, and the calpainprotein which plays a critical role in apoptosis involve in manganese mixture induce apoptosis.Finally, compare the effects of the manganese mixture in breast cancer MDA MB231cells withthe effects in non-tumorigenic MCF10A cells. The results also clearly shows that theseimmortalized breast cells remain unharmed and are insensitive to the cytotoxic effects of themanganese mixture.(4)3,5-diaminobenzoic acid Schiff base complexes are synthesized, and their cellproliferation inhibition activity are studied firstly. The results show that LA5and LC3cadmiumcomplexes have anti-proliferation activity in cancer cells. The experiment also show that LC3potently inhibits chymotrypsin-like activity of20S proteasome and induce apoptosis in humanbreast cancer MDA MB231in dose and time dependent manner; finally, compare the effects of LC3in breast cancer MDA MB231cells with the effects in non-tumorigenic MCF10A cells.These immortalized breast cells remain unharmed and are insensitive to the cytotoxic effects ofLC3. These results support the notion that LC3induce proteasome inhibition, followed byapoptosis induction in breast tumor cells.(5) The study on metformin treatment induced greater levels of growth arrest and cell deathin AR positive PCa cells than AR-negative PCa cells. The results clearly shows AR might play arole in mediating differential sensitivity of PCa cells to metformin. Then investigate the differentAMPK activation profiles in AR-positive and AR-negative PCa cells after metformin or AICARtreatment. The results suggest AR influences AMPK activation profile in response to AMPKactivators in PCa cells and the presence of AR is likely required for prompt and prolong AMPKactivation. In summary, the current study demonstrates that AR is involved in determine thesensitivity of prostate cancer cells to AMPK activator and that prolonged AMPK activation leadsto AR degradation. These findings will help elucidate the role of AMPK in prostate cancer withdifferent genetic background and different pathological stages and eventually promote theclinical application of metformin or other AMPK activator in prostate cancer on a personalizedbasis.