Sodium phenylacetate enhances the inhibitory effect of dextran derivative on breast cancer cell growth in vitro and in nude mice.
Sodium phenylacetate (NaPa) and carboxymethyl benzylamide dextran derivative (CMDB(LS4)) are able to inhibit growth of breast tumour cells. In this study, we explored whether the combination of NaPa and CMDB(LS4)may enhance their respective inhibitory effects on the MCF-7ras cell growth in vitro and in vivo. NaPa inhibited MCF-7ras cell proliferation by reducing the DNA replication concomitantly with a recruitment of cells in G0/G1 phase and by inducing apoptosis in a dose- and time-dependent manner. The addition of CMDB(LS4)potentiated the NaPa antiproliferative effect in the manner dependent on the ratio of CMDB(LS4)and NaPa concentrations. In nude mice, CMDB(LS4)(150 mg kg(-1)) or NaPa (40 mg kg(-1)) administrated twice a week, for 7 weeks inhibited MCF-7ras xenograft growth by 40% and 60%, respectively. The treatment by both, CMDB(LS4)and NaPa, decreased tumour growth by 83% without any toxicity. To better understand the mechanism of NaPa and CMDB(LS4)action we assessed their effect on mitogenic activity of MCF-7ras conditioned medium (CM) on BALBC/3T3 fibroblasts. CMDB(LS4)added to the CM, inhibited its mitogenic activity whereas NaPa had an anti-mitogenic effect when CM was prepared from MCF-7ras cells pretreated with NaPa. Thus, the antiproliferative effects of NaPa and CMDB(LS4)involve 2 different mechanisms explaining, at least in part, the possible synergism between them. Overall, this study points to the potential use of a combination of dextran derivatives with NaPa to inhibit the breast tumour growth.
Di Benedetto
M
M
UPRES 2360, Equipe d'Oncologie cellulaire et moléculaire Université Paris 13, 74 Rue Marcel Cachin, 93017 Bobigny cedex, France.
Kourbali
Y
Y
Starzec
A
A
Vassy
R
R
Jozefonvicz
J
J
Perret
G
G
Crepin
M
M
Kraemer
M
M
D016475:3T3 Cells; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned; D003911:Dextrans / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010648:Phenylacetates / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D017077:Culture Media, Conditioned; D003911:Dextrans; D004338:Drug Combinations; D006133:Growth Substances; D010648:Phenylacetates; C099253:CMDBS 25; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C025136:phenylacetic acid