A novel phenylacetate-dextran derivative (NaPaC) inhibits breast cancer cell proliferation and modifies their interactions with endothelial cells
© BioMed Central Ltd 2001
Received: 10 May 2001
Published: 31 May 2001
Breast cancer treatments are limited by secondary effects and chemoresistances or hormone resistances. Sodium phenylacetate (NaPa), a nontoxic metabolite, has been shown to induce in vivo and in vitro antiproliferative effects on various cell types in our laboratory. We have previously shown that NaPa treatment induced breast tumor cell apoptosis without acquired drug resistance. On the other hand, we have demonstrated that a dextran derivative (CMDB) was not only antitumoral but also antiangiogenic in a MCF-7ras tumor model in animals. Recently, we have synthesized a novel hybrid molecule, CMDB-NaPa ester, called NaPaC, and tested its effect on the proliferation of MDA-MB-231 and MCF-7 breast tumor cells. NaPaC inhibits, dose dependently, the proliferation of MDA-MB-231 cell (IC50 0.5 mmol/l) and of MCF-7 cell (IC50 1.5 mmol/l). Primary cultured endothelial cells (HUVEC) are weakly affected by NaPaC treatment. Cytostatic effect of NaPaC was evidenced from the accumulation of tumor cells in G0/G1 phase after 96 h of treatment.
As compared with the NaPa parent molecule, this new molecule was 10-fold more efficient on these two tumor cell lines. Moreover, NaPaC induces a strong apoptotic effect, as measured with Annexin V-positive cells, on these tumor cells. In order to understand the interactions between tumor cells and endothelial cells, the conditioned media were prepared and added to HUVEC cells. Our results showed a clear killing effect on HUVEC cells. However, this killing effect can be rescued by adding NaPaC.
Taken together, our results showed that NaPaC is a powerful anti-tumoral molecule, with cytostatic and proapoptotic effects on MDA-MB-231 and MCF-7 tumor cells. Further studies should be conducted to better understand the mechanism of these mutual interactions between tumor cells and endothelial cells, especially the killing effect on HUVEC cells.