Interferon β (IFN‐β) is considered a signaling molecule with important therapeutic potential in cancer since IFN‐β‐induced gene transcription mediates antiproliferation and cell death induction. Whereas, TNF‐related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) has emerged as a promising anticancer agent because it induces apoptosis specifically in cancer cells. In this study, we elucidated that IFN‐β augments TRAIL‐induced apoptosis synergistically using five human malignant melanoma cells. All of these cells were induced apoptosis by TRAIL. Whereas, the response against IFN‐β was different in amelanotic cells (A375 and CRL1579) and melanotic cells (G361, SK‐MEL‐28, and MeWo). The responsibility of amelanotic cells against IFN‐β was higher than those of melanotic cells. The synergism of IFN‐β and TRAIL were correlated with the responsibilities of the cells against IFN‐β. The synergistic interaction was confirmed by a combination index based on the Chou‐Talalay method. The upregulation of apoptosis in amelanotic cells was caused by very low doses of IFN‐β (over 0.1 IU/ml). Both of p53‐mediated intrinsic pathway and Fas‐related extrinsic pathway were activated by IFN‐β alone and combination with TRAIL. Further, TRAIL death receptors (DR4 and DR5) were upregulated by a low‐dose IFN‐β (over 0.1 IU/ml) and the expression was more promoted by the combination with TRAIL. It was clarified that the upregulation of DR5 is associated with the declination of viability.

Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon-α2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated. Therefore, the main aim of the present study was to provide further relevant data using two types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT. Dotted accumulations of γH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 µM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the antitumor effect of ribavirin. In addition, based on assessements using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time-lapse, indicating the induction of G0/G1-phase arrest. Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells. Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, downstream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines. These findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin.

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)-α2b and interleukin-2 have been approved for adjuvant immuno-chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN-β has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN-β in malignant melanoma. We evaluated the efficacy of TMZ and IFN-β by comparing O 6-methylguanine-DNA transferase (MGMT)-proficient and-deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor ® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN-β suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN-β enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN-β in combination with TMZ.

Cerebral infarction (CI) caused by middle cerebral artery occlusion exhibits a very high mortality rate. To reduce this rate, a decompressive hemicraniectomy (DHC) is performed clinically based on several randomized trials. In ischemic stroke, a state of malnutrition leads to poor outcomes. However, little evidence is available on nutrition state in the acute phase after DHC. This preliminary study focuses on serum markers, especially dynamic or static nutrition-associated markers including prealbumin, transferrin, retinol binding protein (RBP) and serum albumin under tube feeding with Peptamen®AF (Nestlé Health Science Japan). Blood samples were collected from four patients and analyzed at 6 time points over 14 days (preoperative day, post-operative day (POD) 1, POD 3, POD 7, POD 10, and POD 14). One-way analysis of variance (ANOVA), post hoc Least Significant Difference (LSD), was employed to analyze the blood levels at each time point. The prealbumin and RBP levels showed no significant difference between preoperation and POD 3, although they decreased gradually, while transferrin decreased significantly between the preoperative day and POD 3 (P < 0.05). The level increased significantly on POD 14 as compared to POD 3 (P < 0.05) for each dynamic marker, respectively. The albumin value decreased significantly on POD 3 to POD 7 as compared to the preoperational day (P < 0.05), while the total protein fell significantly on POD 3 (P < 0.05). The total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, glucose, transferrin, and C-reactive protein were also investigated. Some markers fluctuated significantly, especially on POD 3. The duration may represent a hypercatabolic phase for malignant cerebral infarction with DHC. Based on these findings, further investigations among these markers, the tube fed contents, physiological changes and disability could lead to better outcomes following malignant CI.