title: Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana.
abstract: Doxorubicin (Dox) is a potent, broad-spectrum chemotherapeutic drug used around the world. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent pro-oxidant activity. It has been reported that Dox has toxic effects on normal tissues, including brain tissue. The present study tested the protective effect of a xanthone derivative of Garcinia Mangostana against Dox-induced neuronal toxicity. Xanthone can prevent Dox from causing mononuclear cells to increase the level of tumor necrosis factor-alpha (TNFα). We show that xanthone given to mice before Dox administration suppresses protein carbonyl, nitrotyrosine and 4-hydroxy-2'-nonenal (4HNE)-adducted proteins in brain tissue. The levels of the pro-apoptotic proteins p53 and Bax and the anti-apoptotic protein Bcl-xL were significantly increased in Dox-treated mice compared with the control group. Consistent with the increase of apoptotic markers, the levels of caspase-3 activity and TUNEL-positive cells were also increased in Dox-treated mice. Pretreatment with xanthone suppressed Dox-induced increases in all indicators of injury tested. Together, the results suggest that xanthone prevents Dox-induced central nervous system toxicity, at least in part, by suppression of Dox-mediated increases in circulating TNFα. Thus, xanthone is a good candidate for prevention of systemic effects resulting from reactive oxygen generating anticancer therapeutics.
authors.affiliation: School of Allied Health Sciences and Public Health, Thasala, Nakhon-Si-Thammarat, Thailand.
authors.forename: J
authors.initials: J
authors.lastname: Tangpong
authors.forename: S
authors.initials: S
authors.lastname: Miriyala
authors.forename: T
authors.initials: T
authors.lastname: Noel
authors.forename: C
authors.initials: C
authors.lastname: Sinthupibulyakit
authors.forename: P
authors.initials: P
authors.lastname: Jungsuwadee
authors.forename: D K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D029762:Garcinia mangostana / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010936:Plant Extracts; D044004:Xanthones; D004317:Doxorubicin