title: Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.
abstract: BACKGROUND
  Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping.
  
  
  RESULTS
  Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 microM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 microM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 microM), doxorubicin (Dox, 1.12 microM) and 5-fluoruouracil (5-Fu, 0.232 microM) are lower than Pro (5.12 microM), ICRF-187 (129 microM) and MST-16 (26.4 microM), VCR, Dox and 5-Fu shows a low dose-related - high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 microM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia.
  
  
  CONCLUSIONS
  It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs.
authors.affiliation: School of Life Sciences, Shanghai University, Shanghai 200436, PR China. ludayong@sh163.net
authors.forename: Da Yong
authors.initials: DY
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Cheng Hui
authors.initials: CH
authors.lastname: Xu
authors.forename: Wei Yi
authors.initials: WY
authors.lastname: Yang
authors.forename: Chao Xin
authors.initials: CX
authors.lastname: Hu
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Lin Jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Mei Hong
authors.initials: MH
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Xiong Wen
authors.initials: XW
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D020090:Chromosome Segregation / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D011929:Razoxane / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; C055262:probimane; D011929:Razoxane; C057773:sobuzoxane