Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.
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.
Lu
Da Yong
DY
School of Life Sciences, Shanghai University, Shanghai 200436, PR China. ludayong@sh163.net
Huang
Min
M
Xu
Cheng Hui
CH
Yang
Wei Yi
WY
Hu
Chao Xin
CX
Lin
Li Ping
LP
Tong
Lin Jiang
LJ
Li
Mei Hong
MH
Lu
Wei
W
Zhang
Xiong Wen
XW
Ding
Jian
J
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*
D000970:Antineoplastic Agents; D010879:Piperazines; C055262:probimane; D011929:Razoxane; C057773:sobuzoxane