Ascorbic acid derivatives as a new class of antiproliferative molecules

作者：Bordignon Benoit; Chiron Julien; Fontes Michel^*

来源：Cancer Letters, 2013, 338(2): 317-327.

DOI：10.1016/j.canlet.2013.06.015

• Antiproliferative drugs
• Ascorbic acid
• Derivative of ascorbic acid
• Xenograft models

Ascorbic acid (AA) has long been described as an antiproliferative agent. However, the molecule has to be used at a very high concentrations, which necessitates i.v. injection, and the tight regulation of in-blood and in-cell AA concentrations making it impossible to hold very high concentrations for any substantial length of time. %26lt;br%26gt;Here we report evidence that AA derivates are antiproliferative and cytotoxic molecules at an IC50 lower than AA itself. Among these new molecules, we selected K873 that has cytotoxic and antiproliferative effects on different human tumor cells at tenth micromolar concentration. In a further step, we demonstrated that K873 selectively to kills only cancer cells without being toxic for normal non-dividing (or poorly dividing) cells. Finally, we tested the effect of treatment with K873 (5-10 mg/kg/d by i.p. route) on tumor progression in xenografted immunodeficient mice (BALB/c Nude). Our data suggest that K873 administration strongly inhibits tumor progression. In a previous study using microarrays, we demonstrated that AA decreases the expression of two genes families involved in cell cycle progression, i.e. initiation factor of translation and tRNA synthetases. Here we show that K873 treatment also decreases the expression of four of these genes in xenografted tumors, in proportions similar to that previously observed with AA. Taken together, our data suggest that AA and K873 share similar action. %26lt;br%26gt;Our findings suggest that AA derivatives could be a promising new class of anti-cancer drugs, either alone or in combination with other molecules.

• 出版日期2013-9-28