Virotherapy: From single agents to combinatorial treatments.

Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.

Antitumoral potential, antioxidant activity and carotenoid content of two Southern Italy tomato cultivars extracts: San Marzano and Corbarino.

Gastric cancer represents a diffuse and aggressive neoplasm, whose mortality index is among the highest in the world. Predisposing factors are E-cadherin mutations, Helicobacter pylori infection, and a diet rich in salted and smoked food, with a low intake of fresh fruits and vegetables. Here, we analyzed the effect of total lipophilic extracts of two Southern Italy tomato varieties, San Marzano and Corbarino, on an in vitro model of gastric cancer, YCC-1, YCC-2 and YCC-3 cell lines, characterized by different aggressiveness. Our results showed a possible role of these two varieties of tomatoes against typical neoplastic features. The treatment with tomato extracts affected cancer cell ability to grow both in adherence and in semisolid medium, reducing also cell migration ability. No toxic effects were observed on non-tumoral cells. We found, on gastric cancer cell lines, effects on both cell cycle progression and apoptosis modulation. The extent of antineoplastic effects, however, did not seem to correlate with the carotenoid content and antioxidant activity of the two tomato varieties. Our data indicate that San Marzano and Corbarino intake might be further considered as nutritional support not only in cancer prevention, but also for cancer patient diet.

Antineoplastic activity of povidone-iodine on different mesothelioma cell lines: results of in vitro study.

OBJECTIVE: Povidone-iodine (PVP-I) or Betadine, owing to its antineoplastic activity, is also used as an adjuvant during intra-abdominal or intrathoracic surgery. However, the protocol of PVP-I administration has not been optimized to achieve the best antitumoural efficacy. We aimed to determine the optimal concentration of PVP-I, the time of incubation and the mechanism of cell death by analysing the effect of different doses and time of administration of PVP-I on the cell viability of different mesothelioma cell lines. METHODS: Four different cell lines (MET 5A/normal mesothelium; H2052/sarcomatoid mesothelioma; ISTMES2/epithelial mesothelioma; MSTO/biphasic mesothelioma) were incubated with increasing concentrations of diluted PVP-I (0.0001; 0.001; 0.01; 0.1; 1%) for 5, 10, 30, 60 min and 24 h, respectively. Cell viability was determined using cell direct cytotoxicity assay and cell death was determined through flow cytometry assay analysis. The superoxide dismutase activity was assessed functionally through a specific inhibitor to evaluate the mechanism of cell death. RESULTS: The antiproliferative effect of PVP-I varied largely among different cell lines in a dose- and time-dependent manner. At 0.1% concentration for 10 min of incubation, the percentage of viable cells was 0.5 ± 0.1; 0.8 ± 0.5 and 0% (P < 0.01) for MET5A, ISTMES2 and MSTO, respectively. Conversely, the same concentration did not significantly affect the H2052 cell line which was completely suppressed at a 1% concentration of PVP-I. Double staining of Annexin V and DNA showed that PVP-I induced cell death in all four cell lines via necrosis depending on PVP-I concentration. However, H2052 was found to be more resistant than MSTO, ISTMES2 and MET 5A cells lines. The activity of superoxide dismutase was significantly inhibited in all cell lines. CONCLUSIONS: Our results confirmed the anti-neoplastic activity of PVP-I especially on ISTMES2 and MSTO cell lines. With respect to chemotherapy pleural irrigation, washing with PVP-I is cost-effective and easy. If confirmed by larger studies, our findings suggest that the intrapleural irrigation with PVP-I (0.1% concentration for 10 min) in patients with epithelial or biphasic mesothelioma undergoing cytoreductive surgery might be applied in thoracic surgery practice to prevent neoplastic cell growth.

CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy.

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1alpha at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.

Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review).

The medicinal properties of extracts from the hemp plant Cannabis sativa have been known for centuries but only in the 90s membrane receptors for the Cannabis major principle were discovered in mammalian cells. Later on the endogenous ligands for the cannabinoid receptors were identified and the term 'endocannabinoid system' was coined to indicate the complex signaling system of cannabinoid receptors, endogenous ligands and the enzymes responsible for their biosynthesis and inactivation. The 'endocannabinoid system' is involved in a broad range of functions and in a growing number of pathological conditions. There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models. Most work has focused on the role of endocannabinoids in regulating tumor cell growth and apoptosis and ongoing research is addressed to further dissect the precise mechanisms of cannabinoid antitumor action. However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases. The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.