Nuove prospettive terapeutiche del glioma: N6-isopenteniladenosina ed SR141716

2014 - 2015Glioma is a fatal disease characterized by uncontrolled cellular proliferation and it is the most common primary brain malignancy in adults. Despite years of research, malignant glioma remains one of the most aggressive cancer, with an average expectancy of life of 12-15 months after resection, radiotherapy and chemotherapy. N6-isopentenyladenosine (iPA) is a modified nucleoside with a pentaatomic isopentenyl moiety, derived from mevalonate, that induces inhibition of cell proliferation in several tumor cell lines. It has been shown that iPA modulates the expression of several proteins involved in the promotion of tumor growth, but only recently, our studies suggested bone morphogenetic protein 4 (BMP4), part of the transforming growth factor beta superfamily, as potential iPA target. According to preliminary results, infact, iPA, in several human colorectal cancer and glioma cell lines, is able to inhibit cell proliferation and to modulate, in a tumor specific way, the expression of BMP4, involved in the migration, invasion and differentiation of tumor cells. SR141716 is an antagonist of cannabinoids receptor type 1 (CB1), involved in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in physiopathological conditions. Our group showed that a majority of human glioma cell lines overexpresses CB1, compared to normal human astrocytes, and that, in this cancer model, SR141716 is able to induce apopstosis via G1 phase stasis. This study demonstrates also that SR141716 increases the functional and selective expression of MICA/B on the surface of malignant glioma cells through a mechanism that involves STAT3 inhibition. This makes SR141716 treated-glioma cells, a potent target for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism. Although further studies will be necessary to investigate the mechanism of action of these molecules, these results shed new light on the oncogenic networks in the complex biology of glioma. [edited by author]XIV n.s

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumour effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, with minimal toxicity towards normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1μM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracil-induced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the pro-apoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options