Potent in vitro antiproliferative properties for a triplatinum cluster toward triple negative breast cancer cells

The trinuclear platinum cluster [Pt3(μ-PBut2)3(CO)3]CF3SO3 (I) was designed featuring the presence of a nearly equilateral platinum triangle bridged by three di-tert-butylphosphide ligands; in addition, each platinum center bears a terminal carbonyl ligand. This triplatinum cluster was initially developed in view of applications in the field of cluster-containing innovative materials. Yet, due to the large success of platinum complexes in cancer treatment, we also decided to explore its cytotoxic and anticancer properties. Accordingly, the solubility profile of this compound in several solvents was preliminarily investigated, revealing a conspicuous solubility in DMSO and DMSO/buffer mixtures; this makes the biological testing of I amenable. UV–Vis measurements showed that the triplatinum cluster is stable for several hours under a variety of conditions, within aqueous environments. No measurable reactivity was observed for I toward two typical model proteins, i.e. lysozyme and cytochrome c. On the contrary, a significant reactivity was evidenced when reacting I with small sulfur-containing ligands. In particular, a pronounced reactivity with reduced glutathione and cysteine emerged from ESI-MS experiments, proving complete formation of I-GSH and I-Cys derivatives, with the loss of a single carbonyl ligand. Starting from these encouraging results, the cytotoxic potential of I was assayed in vitro against a panel of representative cancer cell lines, and potent cytotoxic properties were disclosed. Of particular interest is the finding that the triplatinum species manifests potent antiproliferative properties toward Triple Negative Breast Cancer Cells, often refractory to most anticancer drugs. Owing to the reported encouraging results, a more extensive biological and pharmacological evaluation of this Pt cluster is now warranted to better elucidate its mode of action

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K+ flux through the human ether-\ue0-gogo- related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the \u3b21 integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the \u3b21 integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with \u3b21 integrins as did closed channels, current flow through hERG1 channelswas necessary to activate the integrin-dependent phosphorylation of Tyr397 in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K+ flow, whereas metastasis of breast cancer cells was reduced when the hERG1/\u3b21 integrin interaction was disrupted. We conclude that the interaction of \u3b21 integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. © 2014 American Association for Cancer Research

Chip-Based and Wearable Tools for Isothermal Amplification and Electrochemical Analysis of Nucleic Acids

The determination of nucleic acids has become an analytical diagnostic method with many applications in fields such as biomedical sciences, environmental monitoring, forensic identification, and food safety. Among the different methods for nucleic acid analysis, those based on the polymerase chain reaction (PCR) are nowadays considered the gold standards. Isothermal amplification methods are an interesting alternative, especially in the design of chip-based architectures. Biosensing platforms hold great promise for the simple and rapid detection of nucleic acids since they can be embedded in lab-on-a-chip tools to perform nucleic acid extraction, amplification, and detection steps. Electrochemical transduction schemes are particularly interesting in the design of small and portable devices due to miniaturization, low-energy consumption, and multianalyte detection capability. The aim of this review is to summarize the different applications of isothermal amplification methods combined with electrochemical biosensing techniques in the development of lab-on-a-chip tools and wearable sensors. Different isothermal amplification methods are revised, and examples of different applications are discussed. Finally, a discussion on patented devices is also included

Chip-Based and Wearable Tools for Isothermal Amplification and Electrochemical Analysis of Nucleic Acids

The determination of nucleic acids has become an analytical diagnostic method with many applications in fields such as biomedical sciences, environmental monitoring, forensic identification, and food safety. Among the different methods for nucleic acid analysis, those based on the polymerase chain reaction (PCR) are nowadays considered the gold standards. Isothermal amplification methods are an interesting alternative, especially in the design of chip-based architectures. Biosensing platforms hold great promise for the simple and rapid detection of nucleic acids since they can be embedded in lab-on-a-chip tools to perform nucleic acid extraction, amplification, and detection steps. Electrochemical transduction schemes are particularly interesting in the design of small and portable devices due to miniaturization, low-energy consumption, and multianalyte detection capability. The aim of this review is to summarize the different applications of isothermal amplification methods combined with electrochemical biosensing techniques in the development of lab-on-a-chip tools and wearable sensors. Different isothermal amplification methods are revised, and examples of different applications are discussed. Finally, a discussion on patented devices is also included