The effect of anserine, a novel biochemical modulator, on the antitumor activity of doxorubicin
Tomomi Sugiyama, Haruna Hatakeyama, Chieko Inoue, Yasuyuki Sadzuka. University of Shizuoka, Shizuoka, Japan.
We have confirmed that theanine, a specific amino acid in green tea, enhanced antitumor activity of doxorubicin (DOX) with the decrease of DOX induced adverse reaction.
This action of theanine was contributed to reduction of DOX efflux from tumor cells caused by suppression of glutamate transporter. This suppression by theanine decreased glutamate uptake, intracellular glutathione synthesis, and glutathione-DOX conjugate level, and subsequently reduced extracellular transport of DOX from tumor cell.
Anserine (â-alanyl-N-methylhistidine) exists in several mammalian tissues, including skeletal muscle and brain at high concentration. Anserine has antioxidative activity and antifatigue effect. We investigated a novel efficacy of anserine on the antitumor activity of DOX, as well as theanine. The effects of anserine on DOX influx or efflux were examined in M5076 ovarian sarcoma cells.
The anserine combination group showed a significant increase in DOX uptake at 60 min after the incubation, as compared with the DOX-alone group and this effect is a concentration-dependent manner. In contrast, anserine did not affect DOX efflux from this tumor cell.
As it was expected that anserine might change the therapeutic efficacy of DOX, the effect of anserine on antitumor activity of DOX were examined in vivo. M5076 ovarian sarcoma cells were subcutaneously transplanted onto the backs of BDF1 mice. DOX ( 2.0 mg/kg/day x 4 days ) and anserine ( 100 mg/kg/day x 4 days ) were intraperitoneally injected in turn to M5076 ovarian sarcoma bearing mice from the 23rd day after inoculation.
Although tumor weight in DOX alone group slightly reduced, compared to that in the non-treated group, the combination of anserine with DOX showed a decrease in tumor weight. The combination of anserine with DOX significantly enhanced the DOX concentration in tumor, by 1.5-fold.
Namely, the increase of DOX-induced antitumor activity by anserine was supported by an increase of DOX concentration in the tumor of anserine combined group. In contrast, no increment of DOX concentrations in normal tissues was observed by anserine combination.
Thus, we concluded that anserine enhanced DOX efficacy without increase of adverse toxicity. In conclusions, it is considered that anserine is a novel and useful modulator for inducing enhancement of antitumor activity of DOX.
There have been a few reports that the intake of foods and their components improved cancer chemotherapy. According to these novel evidences, we hope that foods and/or their components lead to success of cancer chemotherapy.
AACR 2005 Abstract #5119
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