Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: New molecular insight into the mechanism of action

Martínez-Serra, Jordi; Maffiotte, Elena; Martín, Javier; Bex, Teresa; Navarro-Palou, María; Ros, Teresa; Plazas, Joana M.; Vögler, Oliver; Gutiérrez, Antonio; Amat, Juan Carlos; Ramos, Rafael; Saus, Carlos; Gines, Jordi; Alemany, Regina; Diaz, M. Rosete De; Besalduch, Joan

doi:10.1016/j.ejphar.2011.02.035

Cited by 18 publications

(17 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the precise function of trabectedin in sarcomas is unclear, it appears to involve alterations in transcription downstream of histone and transcription factor binding 153 . Trabectedin sensitizes cancer cell lines to FAS-mediated cell death 154 and sarcomas with intact nucleotide excision repair (NER) appear to be more sensitive to the drug than those with dysfunctional NER 155 .…”

Section: Therapeutic Avenuesmentioning

confidence: 99%

Advances in sarcoma genomics and new therapeutic targets

et al. 2011

View full text Add to dashboard Cite

Preface Increasingly, human mesenchymal malignancies are classified by the abnormalities that drive their pathogenesis. While many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities and in many cases are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled to novel therapeutic strategies, have the potential to transform the care of patients with sarcoma.

show abstract

Section: Therapeutic Avenuesmentioning

confidence: 99%

Advances in sarcoma genomics and new therapeutic targets

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Cytotoxic and apoptotic effects of trabectedin has been shown previously in various cancer cell types including leukemia [ 14 ], breast cancer [ 18 ] and lung adenocarcinoma [ 19 ]. However the effect of trabectedin on cancer stem cells is still a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

Enhanced G2/M Arrest, Caspase Related Apoptosis and Reduced E-Cadherin Dependent Intercellular Adhesion by Trabectedin in Prostate Cancer Stem Cells

et al. 2015

View full text Add to dashboard Cite

Trabectedin (Yondelis, ET-743) is a marine-derived tetrahydroisoquinoline alkaloid. It is originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and currently produced synthetically. Trabectedin is active against a variety of tumor cell lines growing in culture. The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs). Cluster of differentiation (CD) 133+high/CD44+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry. We studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs. DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 h and the growth inhibition rates were examined using the sphere-forming assay. Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death. Concentration-dependent effects of trabectedin on the cell cycle were also evaluated. The cells were exposed to the different doses of trabectedin for 24, 48 and 72 h to evaluate the effect of trabectedin on the number and diameter of spheroids. According to the results, trabectedin induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose-dependent manner. Cell cycle analyses revealed that trabectedin induces dose-dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments. Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs. Furthermore, we have found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU-145 and PC-3 CSCs. Our results showed that trabectedin inhibits cellular proliferation and accelerates apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer.

show abstract

“…Studies have suggested that the nucleotide excision repair mechanism may be essential for the antitumor activity of trabectedin and that the resulting double-strand breaks are more persistent if there is loss of homologous repair [ 5 , 6 ]. Evidence shows that disruption of DNA by trabectedin ultimately causes apoptosis and sensitization of cancer cells to Fas-mediated cell death [ 7 ]. Multiple studies, including specific experiments in soft tissue sarcomas, have also validated that trabectedin works at the tumor microenvironment with selective activity against monocytes and tumor-associated macrophages [ 8 , 9 ].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Trabectedin in Soft Tissue Sarcomas

et al. 2015

View full text Add to dashboard Cite

Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.

show abstract

Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: New molecular insight into the mechanism of action

Cited by 18 publications

References 29 publications

Advances in sarcoma genomics and new therapeutic targets

Advances in sarcoma genomics and new therapeutic targets

Enhanced G2/M Arrest, Caspase Related Apoptosis and Reduced E-Cadherin Dependent Intercellular Adhesion by Trabectedin in Prostate Cancer Stem Cells

Trabectedin in Soft Tissue Sarcomas

Contact Info

Product

Resources

About