Prevention of Graft-Versus-Host Disease by a Novel Immunosuppressant, Pg490???88, Through Inhibition of Alloreactive T Cell Expansion

Chen, Benny J.; Liu, Congxiao; Cui, Xiuyu; Fidler, John M.; Chao, Nelson J.

doi:10.1097/00007890-200011270-00008

Cited by 29 publications

(22 citation statements)

References 22 publications

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“…24 Briefly, prior to intracellular cytokine staining, spleen cells were first activated with 10 nM phorbol 12-myristate 13-acetate (PMA; Sigma) and 0.5 M ionomycin (Sigma) for 4 hours in the presence of brefeldin A (10 g/mL; Sigma). Brefeldin A disaggregates the Golgi complex and enables intracellular proteins to accumulate.…”

Section: Intracellular Cytokine Stainingmentioning

confidence: 99%

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation

Chen

Cui

Sempowski

et al. 2004

Blood

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Section: Intracellular Cytokine Stainingmentioning

confidence: 99%

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation

Chen

Cui

Sempowski

et al. 2004

Blood

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“…Although it was considered effective in the treatment of inflammatory or autoimmune disorders by the inhibition of cytokine production Chen et al, 2000;Cibere et al, 2003), triptolide also has an antiproliferative effect for tumor cells in vitro and in vivo (Chang et al, 2001;Jiang et al, 2001;Yang et al, 2003;Fidler et al, 2003;Miyata et al, 2005;Carter et al, 2006;Wan et al, 2006). Among several intracellular pathways suggested to be responsible for the antiproliferative effect of triptolide, the suppression of p21 is one of the most convincing mechanisms (Chang et al, 2001;Fidler et al, 2003) but the details have never been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3b (GSK3b), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3b axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

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“…In the past few years, new watersoluble triptolide derivatives have been designed and synthesized, including PG490-88 or F60008. PG490-88 or F60008, a prodrug of triptolide, is converted to triptolide in vivo by plasma esterases following intravenous administration [59][60][61][62][63][64][65][66][67] . Table 1 summarizes the preclinical pharmacological study of triptolide and PG490-88/F60008 against autoimmune diseases and transplantation rejection.…”

Section: Twhf a Representative Chinese Medicinal Herb Showing Immunomentioning

confidence: 99%

Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

Tang

Zuo

2012

Acta Pharmacol Sin

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The Chinese traditional herb Tripterygium wilfordii Hook f (TwHF) has been widely used in the treatment of autoimmune and inflammatory diseases. Over the past few decades, great efforts have been made to explore modern preparations of TwHF with higher efficacy, solubility, and lower toxicity. In this study, we reviewed several examples both of naturally occurring compounds and their derivatives in TwHF, and summarized the preclinical evaluations with regard to autoimmune and inflammatory diseases. All of the candidate compounds described herein have been or are currently in clinical trials. Although some studies encountered problems, the data still provided valuable references for future studies. (5R)-5-hydroxytriptolide (LLDT-8, Leitengshu) is a novel triptolide derivative with potent immunosuppressive and anti-inflammatory activities developed at Shanghai Institute of Materia Medica. Indeed, a Phase I clinical trial for this compound has been completed in rheumatoid arthritis patients. The results will provide the basis for the further exploration of this ancient herb and encourage the research and development of valuable traditional Chinese medicine. IntroductionFor thousands of years, natural products have played an important role throughout the world in treating and preventing human diseases [1][2][3][4][5] . The discovery and development of immunosuppressants from natural sources have an impressive record: mycophenolic acid (MPA) and cyclosporin A (CsA), the fungal metabolites isolated in 1932 [6] and 1970 [7] , respectively; rapamycin, found in 1975 [8] ; FK506, extracted from a culture filtrate of Streptomyces tsukubaensis in 1987 [9,10] ; and fingolimod (FTY720), described in 1995 [11] . Although the current industry model for drug discovery does not favor natural products, the resources are so vast as to seem unlimited, and these emerging tools will provide important discoveries, leading to new medicines [12] . Furthermore, the drugs already in use as immunosuppressants (eg, cyclophosphamide, methotrexate, azathioprine, cyclosporin) are associated with some significant problems, including toxicity, a lack of reversibility, and increased susceptibility to viral and other infections [13] . Indeed, exploring new and innovative immunosuppres-* To whom correspondence should be addressed.E-mail jpzuo@mail.shcnc.ac.cn Received 2012-06-11 Accepted 2012-07-04 sants from natural sources has now become a focus of intense research.Tripterygium wilfordii Hook f (TwHF) and its extracts have been widely used in the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and dermatomyositis (DM) [14][15][16][17][18] , and have beneficial effects on tissue and organ transplantation [19,20] . In 1993, the ethyl acetate (EA) extract of TwHF was entered into a Phase I study for the treatment of RA patients [21][22][23][24][25] , and many clinical trials have tested triptolide for the treatment of RA and psoriasis [26,27] . In addition, PG490-88/F60008 (F...

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Prevention of Graft-Versus-Host Disease by a Novel Immunosuppressant, Pg490???88, Through Inhibition of Alloreactive T Cell Expansion

Abstract: PG490-88 is highly effective in prevention of murine GVHD. The immunosuppressive effect of PG490-88 is mediated by inhibition of alloreactive T cell expansion through interleukin-2 production.

Cited by 29 publications

References 22 publications

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation

Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

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