[Antitumor effect of sphingosine kinase 1 inhibitor in combination with chemotherapy on SGC7901 gastric cancer cells in vitro].
OBJECTIVE
To study the effect of the sphingosine kinase 1 (SphK1) inhibitor N,N-dimethylsphingosine (DMS) in combination with chemotherapeutic drugs (DDP, 5-Fu, MMC) on the proliferation of gastric cancer cells (SGC7901) in vitro, and to evaluate whether SphK1 inhibitors could be used as synergetic agents in chemotherapy.


METHODS
SGC7901 cells were incubated in vitro with DMS (1 micromol/L) and 5-Fu, DDP, MMC at different concentrations in combination or separately for 24 h. The effects on the growth and survival of SGC7901 cells were determined by MTT assay. The inhibition rates were assessed by response surface analysis and the interactive relationships between the combined drugs were evaluated on the basis of positive/negative values of the cross product coefficients in the response surface equation.


RESULTS
The growth inhibition rate of the gastric cancer cells by treatment with DMS (1 micromol/L) was (10.23 +/- 0.74)%. The growth inhibition rates of the gastric cancer cells treated with 5-Fu (1, 5 and 25 microg/ml) for 24 h were (9.95 +/- 3.24)%, (21.04 +/- 2.19)%, and (45.49 +/- 3.60)%, respectively. The growth inhibition rates of the gastric cancer cells treated with DDP (0.5, 2.5 and 12.5 microg/ml) for 24 h were (9.38 +/- 0.79)%, (19.61 +/- 0.90)%, and (29.83 +/- 0.54)%, respectively. The growth inhibition rates of the gastric cancer cells treated with MMC (0.1, 0.5 and 2.5 microg/ml) for 24 h were (15.35 +/- 0.77)%, (24.72 +/- 0.83)%, and (30.68 +/- 0.28)%, respectively. There were significant differences among the inhibition rates caused by different concentrations of the drugs (P < 0.05). When 1 micromol/L DMS was used in combination with 5-Fu (1, 5, and 25 microg/ml) for 24 h, the growth inhibition rates of the cancer cells were (16.76 +/- 0.41)%, (27.28 +/- 0.29)% and (52.56 +/- 3.60)%, respectively. When 1 micromol/L DMS was used in combination with DDP (0.5, 2.5, and 12.5 microg/ml) for 24 h, the growth inhibition rates of the cancer cells were (15.35 +/- 0.86)%, (25.57 +/- 0.27)%, (36.37 +/- 0.51)%, respectively. When 1 micromol/L DMS was used in combination with MMC (0.1, 0.5, and 2.5 microg/ml) for 24 h, the growth inhibition rates of the cancer cells were (21.02 +/- 0.28)%, (32.10 +/- 0.27)%, (36.36 +/- 0.28)%, respectively. There were also significant differences among the growth inhibition rates caused by different concentrations of the drugs alone and in combination groups (P < 0.05).


CONCLUSIONS
DMS can suppress the proliferation of SGC7901 cells in vitro, and there are evident synergetic effects when it is used in combination with chemotherapeutic drugs. The results of this study indicate that SphK1 inhibitors may become novel and promising chemotherapeutic sensitizers.
Department of Gastroenterology, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Guo-Jian
GJ
Yin
Kang-Hua
KH
Lan
Chuang-Ying
CY
Hu
Qin
Q
Lu
Wen
W
Tang
Shao-Feng
SF
Wang
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000473:pathology*; D000099157:Sphingosine Kinase
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002945:Cisplatin; D004791:Enzyme Inhibitors; D005472:Fluorouracil; D016685:Mitomycin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine