Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals

Abstract

As a well known anti-neoplastic drug, the cytogenotoxicity of methotrexate (MTX) has received more attention in recent years. To develop a new cytoprotector to reduce the risk of second cancers caused by methotrexate, an umu test combined with a micronucleus assay was employed to estimate the cytoprotective effects of ten kinds of bioactive phytochemicals and their combinations. The results showed that allicin, proanthocyanidins, polyphenols, eleutherosides and isoflavones had higher antimutagenic activities than other phytochemicals. At the highest dose tested, the MTX genetoxicity was suppressed by 34.03%∼67.12%. Of all the bioactive phytochemical combinations, the combination of grape seed proanthocyanidins and eleutherosides from Siberian ginseng as well as green tea polyphenols and eleutherosides exhibited stronger antimutagenic effects; the inhibition rate of methotrexate-induced genotoxicity separately reached 74.7 ± 6.5% and 71.8 ± 4.7%. Pretreatment of Kunming mice with phytochemical combinations revealed an obvious reduction in micronucleus and sperm abnormality rates following exposure to MTX (p < 0.01). Moreover, significant increases in thymus and spleen indices were observed in cytoprotector candidates in treated groups. The results indicated that bioactive phytochemicals combinations had the potential to be used as new cytoprotectors.

Beneficial role of virgin coconut oil supplementation against acute methotrexate chemotherapy-induced oxidative toxicity and inflammation in rats

“… 5 , 6 The action mechanism of MTX inhibits dihydrofolate reductase and thymidylate synthase involved in the synthesis of DNA precursors such as thymidylates and purines. 7 The inhibition impairs DNA synthesis, DNA repair mechanism and replication during the S-phase of cell cycle in rapidly dividing cells including cancer cells and some normal dividing cells. 6 …”

Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis

“…Its main ingredients are ginseng and ginger root, which help DKT regulate the activity of the intestine and reduce the dysfunction of the small intestine [ 44 ]. Some researchers have screened cytoprotective agents against MTX-induced cell genotoxicity from among biologically active phytochemicals and found that agents, such as Siberian ginseng and curcumin have cytoprotective effects [ 45 ]. Total ginsenosides was reported to promote intestinal epithelial cell proliferation, presumably via the regulation of the cell cycle and of the expression of proliferation-related proteins by polyamines [ 46 ].…”

Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis

“…Its main ingredients are ginseng and ginger root, which help DKT regulate the activity of the intestine and reduce the dysfunction of the small intestine 14 . Some researchers have screened cytoprotective agents against MTX-induced cell genotoxicity from among biologically active phytochemicals and found that agents such as Siberian ginseng and curcumin have cytoprotective effects 59 . Total ginsenosides was reported to promote intestinal epithelial cell proliferation, presumably via the regulation of the cell cycle and of the expression of proliferation-related proteins by polyamines 60 .…”