Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Publication year range
1.
Anticancer Res ; 34(10): 5287-94, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25275021

ABSTRACT

BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor. MATERIALS AND METHODS: The potential of combining the Bcl-2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-XL, and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T-lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated. RESULTS: ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1-Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti-apoptotic molecule that confers drug resistance on ATL cells. CONCLUSION: The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL.


Subject(s)
Biphenyl Compounds/pharmacology , Boronic Acids/pharmacology , Hydroxamic Acids/pharmacology , Leukemia-Lymphoma, Adult T-Cell/metabolism , Nitrophenols/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrazines/pharmacology , Sulfonamides/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Bortezomib , Cell Line, Tumor , Cell Survival/drug effects , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/genetics , Piperazines/pharmacology , Proteasome Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/genetics , Vorinostat
2.
J Nat Med ; 67(2): 415-20, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22961603

ABSTRACT

Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4ß-hydroxy group as well as a 5ß,6ß-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.


Subject(s)
Solanaceae/chemistry , Withanolides/chemistry , Withanolides/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Humans , Leukemia-Lymphoma, Adult T-Cell/metabolism , Molecular Structure , Structure-Activity Relationship
3.
Cancer Lett ; 317(2): 218-25, 2012 Apr 28.
Article in English | MEDLINE | ID: mdl-22138435

ABSTRACT

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). ABT-737, a small molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, significantly induced apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells, and synergistically enhanced the cytotoxicity and apoptosis induced by conventional cytotoxic drugs. Moreover, ABT-737 significantly inhibited the in vivo tumor growth of an ATLL mouse model. These results suggest that the use of an agent targeting anti-apoptotic bcl-2 family proteins, either alone or in combination with other conventional drugs, represents a novel promising approach for ATLL.


Subject(s)
Biphenyl Compounds/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Nitrophenols/therapeutic use , Sulfonamides/therapeutic use , Xenograft Model Antitumor Assays , Adult , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/metabolism , Biphenyl Compounds/pharmacology , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Female , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/physiology , Humans , Immunohistochemistry , Jurkat Cells , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathology , Mice , Mice, SCID , Nitrophenols/pharmacology , Piperazines/pharmacology , Piperazines/therapeutic use , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Tumor Burden/drug effects , bcl-X Protein/antagonists & inhibitors , bcl-X Protein/metabolism
4.
Anticancer Res ; 31(7): 2483-8, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21873163

ABSTRACT

The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL.


Subject(s)
Antineoplastic Agents/pharmacology , Bacterial Proteins/pharmacology , Diphtheria Toxin/pharmacology , Growth Inhibitors/pharmacology , Intercellular Signaling Peptides and Proteins/biosynthesis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Bacterial Proteins/administration & dosage , Breast Neoplasms/pathology , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Diphtheria Toxin/administration & dosage , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Drug Synergism , ErbB Receptors/biosynthesis , Gene Expression Regulation, Neoplastic/drug effects , Genes, erbB-1 , Growth Inhibitors/administration & dosage , Heparin-binding EGF-like Growth Factor , Humans , Jurkat Cells/drug effects , Jurkat Cells/metabolism , Ligands , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Protein Kinase Inhibitors/administration & dosage , Signal Transduction/drug effects
5.
Int J Hematol ; 92(5): 762-4, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21080125

ABSTRACT

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan.


Subject(s)
Antineoplastic Agents/therapeutic use , Interferon-alpha/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Zidovudine/therapeutic use , Antineoplastic Agents/adverse effects , Drug Therapy, Combination , Female , Humans , Interferon-alpha/adverse effects , Japan , Male , Middle Aged , Pilot Projects , Receptors, Interleukin-2/blood , Recurrence , Treatment Outcome , Zidovudine/adverse effects , Zidovudine/blood
6.
Rinsho Ketsueki ; 51(6): 422-6, 2010 Jun.
Article in Japanese | MEDLINE | ID: mdl-20622489

ABSTRACT

A 72-year-old man with extranodal natural killer cell lymphoma (ENKL) presented with a painless swelling of the left forearm. He was initially diagnosed as having a bacterial cellulitis and received antimicrobial therapy. However, his left arm became increasingly swollen in association with fever and redness of the lesion. Therefore, he underwent focal dissection. Because of persistent swelling, the left arm was rebiopsied 9 months later, and a diagnosis of ENKL developing in the subcutis was established. He was treated with focal radiation therapy in combination with dexamethasone, etoposide, ifosfamide, methotrexate and L-asparaginase. The lesion was significantly reduced in size but did not disappear completely. Two months later the lesion became necrotic, although swelling of the forearm lesion, left axillary and cervical lymph nodes were kept under control. We then performed amputation of the left forearm since it could not be saved medically. The patient currently remains alive and well without progression 2 years after amputation. When evaluating panniculitis, which is difficult to cure, ENKL should be considered in the differential diagnosis and treated appropriately.


Subject(s)
Forearm , Killer Cells, Natural/pathology , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/therapy , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/therapy , Aged , Amputation, Surgical , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Diagnosis, Differential , Humans , Lymphoma, T-Cell/pathology , Male , Radiotherapy, Adjuvant , Soft Tissue Neoplasms/pathology , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...