Protective effect of the immunomodulator AS101 against cyclophosphamide-induced testicular damage in mice.
BACKGROUND
Cyclophosphamide (Cy), a widely used anticancer drug, is associated with significant testicular damage and sterility. Co-administration of the immunomodulating compound AS101 during chemotherapy treatments was previously shown to protect organs against cytotoxic damage, without attenuating the drug's anticancer effect. In this animal study, we investigated the effect of AS101 on testicular damage, sperm DNA damage and infertility induced by Cy. Akt and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation were investigated as a possible chemoprotective mechanism.


METHODS
Mature male mice, 10 in each group, were injected intraperitoneally with 200 mg/kg Cy once a week for 5 weeks, with or without concurrent treatment with 10 microg per mouse AS101 three times per week. Damage to testicular tubules and sperm production was determined, sperm chromatin damage was analyzed and fertility was gauged. Akt and GSK-3beta phosphorylation were evaluated.


RESULTS
Co-treatment with AS101 during the course of Cy administration significantly reduced the percentage of damaged seminiferous tubules (76.0 +/- 10.8% versus 40.3 +/- 2.6%), and reduced sperm DNA fragmentation (%DFI) from 44.7 +/- 1.0% to 25 +/- 6.5%. Co-treatment with AS101 also partially protected against the decrease in numbers of impregnated females and litter size. AS101 increased Akt and GSK-3beta phosphorylation.


CONCLUSIONS
Our results indicate that AS101 can significantly protect against Cy-induced testicular damage and sperm DNA damage, probably by acting through Akt/GSK-3beta phosphorylation.
Carmely
A
A
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Meirow
D
D
Peretz
A
A
Albeck
M
M
Bartoov
B
B
Sredni
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D053938:DNA Fragmentation / Q000187:drug effects; D004347:Drug Interactions; D005030:Ethylenes / Q000494:pharmacology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007248:Infertility, Male / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013076:Sperm Count; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000473:pathology
D000276:Adjuvants, Immunologic; D018906:Antineoplastic Agents, Alkylating; D005030:Ethylenes; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D003520:Cyclophosphamide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3