Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasing apoptosis and chemo-sensitivity. This review focuses on the link between inflammation and cancer by describing the anti-inflammatory agents used in cancer therapy, and their mechanisms of action, emphasizing the use of novel anti-inflammatory agents with significant anticancer activity.

Gemcitabine (GEM, 2′,2′-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells.

Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths worldwide. Sorafenib is the only approved drug for patients with advanced HCC but has shown limited activity. microRNAs (miRs) have been involved in several neoplasms including HCC suggesting their use or targeting as good tools for HCC treatment. The purpose of this study was to identify novel approaches to sensitize HCC cells to sorafenib through miRs. miR-423-5p was validated as positive regulator of autophagy in HCC cell lines by transient transfection of miR and anti-miR molecules. miR-423-5p expression level was evaluated by real-time polymerase chain reaction (PCR) in sera collected from 39 HCC patients before and after treatment with sorafenib. HCC cells were cotreated with sorafenib and miR-423-5p and the effects on cell cycle, apoptosis, and autophagy were evaluated. Secretory miR-423-5p was upregulated both in vitro and in vivo by sorafenib treatment and its increase was correlated with response to therapy since 75% of patients in which an increase of secretory miR423-5p was found were in partial remission or stable disease after 6 moths from the beginning of therapy. HCC cells transfected with miR-423-5p showed an increase of cell percentage in S-phase of cell cycle paralleled by a similar increase of autophagic cells evaluated at both fluorescence activated cell sorter (FACS) and transmission electron microscopy. Our results suggest the miR423-5p can be used as a useful tool to predict response to sorafenib in HCC patients and is involved in autophagy regulation in HCC cells.

Background: Cardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil(5-FU) and it can have detrimental effects both in patients and workers involved in the preparation of chemotherapy. Methods: Specifically, we have assessed the effects of increasing concentrations of 5-FU and doxorubicin (DOXO) on proliferation of H9c2 rat cardiocytes and HT-29 human colon adenocarcinoma cells by MTT assay. Cells were treated for 24, 48 and 72 h with different concentrations of the two drugs alone or with 5-FU in combination with 10^-4 M of levofolene (LF). Results: 5-FU induced a time- and dose-dependent growth inhibition in both cell lines. The 50% growth inhibition (IC:50) was reached at 72 h with concentrations of 4 μM and 400 μM on HT-29 and H9c2, respectively. The addition of LF to 5-FU enhanced this effect. On the other hand, the IC:50 of DOXO was reached at 72 h with concentrations of 0.118 μM on H9c2 and of 0.31 μM for HT-29. We have evaluated the cell death mechanism induced by 50% growth inhibitory concentrations of 5-FU or DOXO in cardiocytes and colon cancer cells. We have found that the treatment with 400 μM 5-FU induced apoptosis in 32% of H9c2 cells. This effect was increased by the addition of LF to 5-FU (38% of apoptotic cells). Apoptosis occurred in only about 10% of HT-29 cells treated with either 5-FU or 5-FU and LF in combination. DOXO induced poor effects on apoptosis of both H9c2 and HT-29 cells (5–7% apoptotic cells, respectively). The apoptosis induced by 5-FU and LF in cardiocytes was paralleled by the activation of caspases 3, 9 and 7 and by the intracellular increase of O²⁻ levels. Conclusions: These results suggest that cardiotoxic mechanism of chemotherapy agents are different and this disclose a new scenario for prevention of this complication.

Head and neck carcinoma (HNC) is a heterogeneous disease encompassing a variety of tumors according to the origin. Laryngeal cancer (LC) represents one of the most frequent tumors in the head and neck region. Despite clinical studies and advance in treatment, satisfactory curative strategy has not yet been reached. Therefore, there is an urgent need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as suitable therapeutic targets. Long non-coding RNAs (lncRNA) are reported as important regulators of gene expression and represent an innovative pharmacological application as molecular biomarkers in cancer. The purpose of this review is to discuss the most relevant epigenetic and histological prognostic biomarkers in HNC, with particular focus on LC. We summarize the emerging roles of long non-coding RNAs in HNC and LC development and their possible use in early diagnosis.

Anti-PD-1/PD-L1 drugs are effective as monotherapy in a proportion of NSCLC patients and there is a strong rationale for combining them with targeted therapy. Inhibition of MAPK pathway may have pleiotropic effects on the microenvironment. This work investigates the efficacy of combining MEK and PD-L1 inhibition in pre-clinical and ex-vivo NSCLC models. We studied the effects of MEK inhibitors (MEK-I) on PD-L1 and MCH-I protein expression and cytokine production in vitro in NSCLC cell lines and in PBMCs from healthy donors and NSCLC patients, the efficacy of combining MEK-I with anti-PD-L1 antibody in ex-vivo human spheroid cultures obtained from fresh biopsies from NSCLC patients in terms of cell growth arrest, cytokine production and T-cell activation by flow cytometry. MEK-I modulates in–vitro the immune micro-environment through a transcriptionally decrease of PD-L1 expression, enhance of MHC-I expression on tumor cells, increase of the production of several cytokines, like IFNγ, IL-6, IL-1β and TNFα. These effects trigger a more permissive anti-tumor immune reaction, recruiting immune cells to the tumor sites. We confirmed these data on ex-vivo human spheroids, showing a synergism of MEK and PD-L1 inhibition as result of both direct cancer cell toxicity of MEK-I and its immune-stimulatory effect on cytokine secretion profile of cancer cells and PBMCs with the induction of the ones that sustain an immune-reactive and inflammatory micro-environment. Our work shows the biological rationale for combining immunotherapy with MEK-I in a reproducible ex-vivo 3D-culture model, useful to predict sensitivity of patients to such therapies.