Therapeutic effect of anthracene-based anticancer agent ethonafide in an animal model of multiple sclerosis.
The side effects of cancer chemotherapeutic agents such as mitoxantrone (MIT) in multiple sclerosis (MS) patients justify the search for less toxic drugs. Ethonafide is an anthracene-based antineoplastic drug similar to MIT. With reference to MIT, we examined the effect of ethonafide on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, an animal model of human MS. We demonstrated that ethonafide is effective in preventing development of EAE as well as in ameliorating the severity of EAE when disease is ongoing. In relatively higher dosages, the effects of ethonafide and MIT on EAE were identical, whereas in lower dosages, MIT seemed more effective. Therapeutic effects of ethonafide were associated with the initial reduction in cellular counts of CD3(+), CD4(+), CD8(+), B220(+), CD11b(+), NK cells, and NKT cells, followed by recovery of these cells from the bone marrow. Interestingly, the recovered autoreactive T cells in ethonafide-treated animals have reduced capacity to expand and produce cytokines in response to myelin Ag stimulation. Furthermore, CD4(+)CD25(+) regulatory T cells were relatively resistant to depletion and/or recovered faster than T effector cells. The ability of regulatory T cells to resist depletion and replenish quickly during cell ablation therapy may provide an opportunity to reprogram the immune system. Moreover, we provided evidences that ethonafide has less cardiac toxicity compared with MIT. The effectiveness and the low cardiotoxicity of ethonafide might make it a promising immunosuppressive agent for clinical use in treating MS patients.
Piao
Wen-Hua
WH
Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Wong
Rudy
R
Bai
Xue-Feng
XF
Huang
Jianhua
J
Campagnolo
Denise I
DI
Dorr
Robert T
RT
Vollmer
Timothy L
TL
Shi
Fu-Dong
FD
D000208:Acute Disease; D000818:Animals; D000873:Anthracenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D007114:Immunization; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
D000873:Anthracenes; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D007546:Isoquinolines; D008942:Mitoxantrone; C034020:anthracene; C521335:2-(2'-(dimethylamino)ethyl)-1,2-dihydro-7-ethoxydibenz(de,h)isoquinoline-1,3-dione