Disulfide-mediated apoptosis of human T-lymphotrophc virus type-I (HTLV-I)-infected cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.
BACKGROUND
This study was conducted to construct a basis for a therapeutic strategy against human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a compound that contained a disulfide moiety, prosultiamine, which is a homologue of allithiamine originally synthesized by allicin and thiamine-thiol, for the targeting of HTLV-I-infected cells.


METHODS
First, we analysed the apoptotic pathway in allicin or prosultiamine treatment against an HTLV-I-infected T-cell line (HCT-1), derived from an HAM/TSP patient, by flow cytometry and western blot. Second, we evaluated the effect of targeting HTLV-I-infected cells in a prosultiamine in vitro treatment and in a clinical trial in HAM/TSP patients by quantitative PCR analysis of HTLV-I proviral load.


RESULTS
Prosultiamine, like allicin, induced caspase-dependent apoptosis against HCT-1 cells. The fact that the loss of mitochondrial membrane potential was recovered in z-VAD-fmk-pretreated HCT-1 cells with prosultiamine treatment suggested that prosultiamine can induce caspase-dependent apoptosis through the mitochondrial pathway. On the basis of data showing that prosultiamine in vitro treatment against peripheral blood CD4(+) T-cells of HAM/TSP patients induced a significant decrease of HTLV-I proviral copy numbers by apoptosis of HTLV-I-infected cells, we treated six HAM/TSP patients with intravenous administration of prosultiamine for 14 days. As a result of this treatment, the copy numbers of HTLV-I provirus in peripheral blood decreased to approximately 30-50% of their pretreatment levels with some clinical benefits in all patients.


CONCLUSIONS
Our results suggest that prosultiamine has the potential to be a new therapeutic tool that targets HTLV-I-infected cells in HAM/TSP.
Nishiura
Yoshihiro
Y
First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Nakamura
Tatsufumi
T
Fukushima
Naomi
N
Nakamura
Hideki
H
Ida
Hiroaki
H
Aramaki
Toshiyuki
T
Eguchi
Katsumi
K
D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004220:Disulfides / Q000494:pharmacology*; D005260:Female; D015490:HTLV-I Infections / Q000150:complications*; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000188:drug therapy*; D013118:Spinal Cord Diseases / Q000188:drug therapy; D013441:Sulfinic Acids / Q000737:chemistry / Q000627:therapeutic use; D013831:Thiamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
D019380:Anti-HIV Agents; D004220:Disulfides; D013441:Sulfinic Acids; C006452:allicin; C013294:prosultiamine; D013831:Thiamine