Non-small cell lung cancers (NSCLCs) are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70) expression and function, together with the induction of lysosomal membrane permeabilization (LMP), could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450) on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxel-and oxaliplatin-resistant subcutaneous human NCI-H727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/TonEBP (a factor responsible for the transcriptional control of Hsp70). These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.

The rapid increase in the incidence of malignant melanomas has not been associated with improved therapeutic options over the years. Indeed melanomas have proven resistant to apoptosis (type I programmed cell death (PCD)) and consequently to most chemotherapy and immunotherapy. It is believed that this resistance can be partly overcome by proautophagic drugs inducing type II (autophagy) PCD. Change at the genomic, transcriptional, and post-translational level of G-proteins and protein kinases, including Ras, plays an important role in the ability of melanomas to resist apoptosis. Ras transformation itself requires membrane anchorage and the overexpression of galectin-1 increases membrane-associated Ras. In this study, it has been found that decreasing galectin-1 expression in B16F10 mouse melanoma cells in vitro by means of an anti-galectin-1 small interfering RNA approach does not modify their sensitivity to type I and type II PCD. However, it does induce heat shock protein 70-mediated lysosomal membrane permeabilization, a process associated with cathepsin B release into the cytosol, which in turn is believed to sensitize the cells to the proautophagic effects of temozolomide when grafted in vivo. Furthermore, temozolomide when compared to the proapoptotic drug cisplatin, significantly increased the survival times of mice in the B16F10 melanoma model.

This study demonstrates that thyroid FNA can be analysed successfully by NGS. The detection of mutations known to be involved in thyroid cancer improves the sensitivity of thyroid FNA diagnosis.

Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter's therapeutic benefit in glioma patients.