Sodium phenylacetate enhances the inhibitory effect of dextran derivative on breast cancer cell growth in vitro and in nude mice

Abstract

Summary 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.

A Mechanistic Approach to Anticancer Therapy: Targeting the Cell Cycle with Histone Deacetylase Inhibitors

“…The SCFAs, including sodium butyrate, sodium phenylbutyrate, sodium phenylacetate, and the butyric acid analog pivaloyloxymethylbutyrate have all been shown to have antitumor activity in animal models [124][125][126][127][128][129]. Their activity has been limited by their potency as HDAC inhibitors, with millimolar concentrations required for enzyme inhibition, and their relatively short half-lives in vivo.…”

New Experimental Therapies Targetting Breast Cancer Cell

“…The comparison of IC50 for three drugs supplies the additional evidence for the highly enhanced efficiency of NaPaC as compared to CMDB and NaPa (Table 2). Therefore, the hybrid molecule retains at least the additive effect of its two components observed previously (Di Benedetto et al, 2001). This effect is not only specifc to MCF-7 ras cells as similar results are obtained for other breast cancer cell lines, including MCF-7, MDA-MB-231 and MDA-MB-435.…”

“…NaPa molecule enhances, in a synergistic or additive manner, the inhibitory effect of CMDB on breast cancer cell growth in vitro and in nude mice when administrated at a CMDB/NaPa ratio of 4 (Di Benedetto et al, 2001). To obtain a new drug with the same properties but easier to use as a future anti-cancer molecule than the combined treatment, we have performed the esterification of CMDB by NaPa respecting the synergistic CMDB/NaPa ratio.…”

Cytotoxic effects of kinetin riboside on mouse, human and plant tumour cells

“…The riboside conjugate should allow binding of kinetin to specific sites on plant and animal tumour cells, and can enhance the inhibitory effect of kinetin, as it was described for sodium acetate and dextran derivative on breast cancer cells [18].…”