Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Soft tissue sarcomas are less responsive to conventional chemotherapy when compared to bone sarcomas. We investigated the possibility of enhancing the efficacy of chemotherapy by utilising the recently identified cytokine, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) in combination with standard chemotherapeutic agents. Fresh human soft tissue sarcomas (rhabdomyosarcoma, fibrosarcoma, malignant fibrous histiocytoma) were obtained at biopsy and dispersed tumour cells were incubated in cell culture with standard cytotoxic agents, either as single agents or in combination with TRAIL. The chemotherapeutic agents were, at best, moderately effective, in terms of induction of cellular apoptosis, although the fibrosarcoma was completely unresponsive to all single agents. TRAIL alone had no effect on any sarcoma cell culture. In contrast, the addition of TRAIL and drug together produced a significant increase in sarcoma cell apoptosis, with TRAIL and doxorubicin the most effective combination.
 ...
PMID:Enhanced apoptosis of soft tissue sarcoma cells with chemotherapy: A potential new approach using TRAIL. 1211 26

Five human soft tissue sarcoma (STS) cell lines (HTB-82 rhabdomyosarcoma, HTB-91 fibrosarcoma, HTB-92 liposarcoma, HTB-93 synovial sarcoma and HTB-94 chondrosarcoma) were analysed for their sensitivity to tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the function of the TRAIL apoptotic pathway in these cells. TRAIL induced significant apoptosis (>90%) in HTB-92 and HTB-93 cells, whereas no effect was observed in HTB-82, HTB-91 and HTB-94 cells. TRAIL-Receptor 1 (TRAIL-R1) was expressed in TRAIL-sensitive HTB-92 and HTB-93 cell lines, but not in TRAIL-resistant HTB-91 and HTB-94 cells. HTB-82 cells, which expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP), were resistant to TRAIL in spite of the presence of TRAIL-R1. TRAIL-R2,-R3,-R4 and osteoprotegerin (OPG) expression did not correlate with TRAIL sensitivity. Coincubation of TRAIL and doxorubicin led to the overexpression of TRAIL-R2 resulting in a synergistic effect of doxorubicin and TRAIL in TRAIL-sensitive cell lines and in the overcoming of TRAIL-resistance in all of the TRAIL-resistant cell lines, except HTB-91, which lacked caspase 8 expression. These data suggest that TRAIL, either as a single agent or in combination with cytotoxic agents, might represent a new treatment option for advanced STS, which constitutes a largely chemotherapy-resistant disease.
 ...
PMID:Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines. 1276 23

B-cell activating factor (BAFF) is a type II transmembrane glycoprotein belonging to the tumour necrosis factor ligand superfamily. Active soluble forms of BAFF are generated either by cleavage of the extracellular domain or by recombinant DNA technology. The current bioassay for measuring the activity of soluble BAFF involves stimulation of the proliferation of mouse splenic B-cells in the presence of goat anti-mouse IgMmicro chain which is rather cumbersome and lengthy and yields variable results. We have therefore developed an alternative functional assay which relies on the ability of BAFF to induce an apoptotic response in human rhabdomyosarcoma cells. For this, we constructed a chimeric receptor containing the ectodomain of the MuBAFF-R--the major cell receptor for BAFF--and the endodomain of the HuTRAIL-R2--one of the two functional receptors for TRAIL--which is known to contain a death domain and trigger apoptosis. When the chimeric receptor was expressed in the TRAIL-sensitive human rhabdomyosarcoma cell line KD4 clone 21, recombinant BAFF of either human or mouse sequence stimulated apoptosis, similar to TRAIL, in a dose-dependent manner. The transfected cell population, called FL17, expressing the MuBAFF-R/ HuTRAIL-R2 thus provided the basis of a novel functional bioassay for BAFF that is simple and relatively fast to perform. The construction of the chimeric receptor, development of the transfected cells expressing this receptor and the development of sensitive and reproducible bioassays for BAFF and anti-BAFF neutralising antibodies are described.
 ...
PMID:A novel bioassay for B-cell activating factor (BAFF) based on expression of a BAFF-receptor ectodomain-tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 endodomain fusion receptor in human rhabdomyosarcoma cells. 1862 9

Resistance of human cancers to current treatment approaches remains a challenge in oncology. Therefore, there has been much interest in identifying molecular pathways that are responsible for primary or acquired resistance of cancers. Since most anticancer therapies, i.e. chemotherapy or radiotherapy, primarily act by triggering programmed cell death (apoptosis) in cancer cells, defects in apoptosis programs may confer resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by the dominance of cell survival pathways, for example aberrant activation of the PI3K/Akt/mTOR cascade, or alternatively, by defective expression or function of critical mediators of apoptosis, i.e. components of the TRAIL signaling system. In addition, signaling to apoptosis can be blocked under hypoxia, a characteristic feature of most solid tumors including rhabdomyosarcoma that has been associated with poor treatment response. Thus, molecular targeted therapies that are specifically directed to the defects in apoptosis programs, open novel perspectives to restore apoptosis sensitivity in rhabdomyosarcoma.
 ...
PMID:Targeting apoptosis resistance in rhabdomyosarcoma. 1878 99

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5.
 ...
PMID:Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma. 2257 81

Maduramicin, a polyether ionophore antibiotic derived from the bacterium Actinomadura yumaensis, is currently used as a feed additive against coccidiosis in poultry worldwide. It has been clinically observed that maduramicin can cause skeletal muscle and heart cell damage, resulting in skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. However, the mechanism of its toxic action in myoblasts is not well understood. Using mouse myoblasts (C2C12) and human rhabdomyosarcoma (RD and Rh30) cells as an experimental model for myoblasts, here we found that maduramicin inhibited cell proliferation and induced cell death in a concentration-dependent manner. Further studies revealed that maduramicin induced accumulation of the cells at G0/G1 phase of the cell cycle, and induced apoptosis in the cells. Concurrently, maduramicin downregulated protein expression of cyclin D1, cyclin-dependent kinases (CDK4 and CDK6), and CDC25A, and upregulated expression of the CDK inhibitors (p21Cip1 and p27Kip1), resulting in decreased phosphorylation of Rb. Maduramicin also induced expression of BAK, BAD, DR4, TRADD and TRAIL, leading to activation of caspases 8, 9 and 3 as well as cleavage of poly ADP ribose polymerase (PARP). Taken together, our results suggest that maduramicin executes its toxicity in myoblasts at least by inhibiting cell proliferation and inducing apoptotic cell death.
...
PMID:Maduramicin inhibits proliferation and induces apoptosis in myoblast cells. 2553 67

TCEA3 is one of three genes representing the transcription elongation factor TFIIS family in vertebrates. TCEA3 is upregulated during skeletal muscle differentiation and acts to promote muscle specific gene expression during myogenesis. Rhabdomyosarcoma (RMS) is a pediatric cancer derived from the muscle lineage, but the expression or function of TCEA3 in RMS was uncharacterized. We found that TCEA3 expression was strongly inhibited in RMS cell lines representing both ERMS and ARMS subtypes of RMS. TCEA3 expression correlates with DNA methylation and we show that TBX2 is also involved in the repression of TCEA3 in RMS cell lines. Ectopic expression of TCEA3 inhibited proliferation of RMS cell lines and initiated apoptosis through both the intrinsic and extrinsic pathways. We found that only pan-caspase inhibitors could block apoptosis in the presence of TCEA3. While expression of TCEA3 is highest in skeletal muscle, expression has been detected in other tissues as well, including breast, ovarian and prostate. We found that ectopic expression of TCEA3 also promotes apoptosis in HeLa, MCF7, MDA-231, and PC3 cell lines, representing cervical, breast, and prostate cancer, respectively. Restoration of TCEA3 expression in RMS cell lines enhanced sensitivity to chemotherapeutic drugs, including TRAIL. Thus, TCEA3 presents a novel target for therapeutic strategies to promote apoptosis and enhance sensitivity to current chemotherapeutic drugs.
 ...
PMID:The transcription elongation factor TCEA3 induces apoptosis in rhabdomyosarcoma. 3198 7