[Show abstract][Hide abstract] ABSTRACT: Plasma membrane integrity is essential for cell life. Any major break on it immediately induces the death of the affected cell. Different molecules were described as disrupting this cell structure and thus showing antitumor activity. We have previously defined that elisidepsin (Irvalec<sup>®</sup>, PM02734) inserts and self-organizes in the plasma membrane of tumor cells, inducing a rapid loss of membrane integrity, cell permeabilization and necrotic death. Here we show that, in sensitive HCT-116 colorectal cells, all these effects are consequence of the interaction of elisidepsin with glycosylceramides in the cell membrane. Of note, an elisidepsin-resistant subline (HCT-116-Irv) presented reduced levels of glycosylceramides and no accumulation of elisidepsin in the plasma membrane. Consequently, drug treatment did not induce the characteristic necrotic cell death. Furthermore, GM95, a mutant derivative from B16 mouse melanoma cells lacking ceramide glucosyltransferase (UGCG) activity and thus the
PLoS ONE 10/2015; 10(10-10):e0140782. DOI:10.1371/journal.pone.0140782 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
[Show abstract][Hide abstract] ABSTRACT: In any disease, the knowledge of the natural history of untreated cases provides a real background against which the real advantages of a new treatment itself are judged. Fortunately, in the present days, there are scant data on outcomes in patients with untreated breast cancer. In an attempt to provide this background against which the virtues of current curative and palliative treatments can be more accurately assessed, we have reviewed the literature regarding published untreated breast cancer series. Taking into consideration all the difficulties of analyzing reports written on the last half of the nineteenth century or on the first half of the twentieth century, in most reports, patients survived almost 3–4 years without any type of treatment. Worth mentioning, approximately 5–10 % of untreated patients lived longer than 10 years. Thus, the spectrum of clinical aggressiveness of untreated breast cancer varies between virulence and chronic disease.
These facts should be taken into account when considering the value of current treatments for early-stage disease.
Medical Oncology 02/2015; 32(2):466. DOI:10.1007/s12032-014-0466-x · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.British Journal of Cancer advance online publication 22 April 2014; doi:10.1038/bjc.2014.149 www.bjcancer.com.
British Journal of Cancer 04/2014; 111(4). DOI:10.1038/bjc.2014.149 · 4.84 Impact Factor