Adenovirus as a Vector and Oncolytic Virus.

Adenoviral vectors, both oncolytic viruses and gene delivery vectors, are among the earliest approved and commercialised vectors for gene therapy. Adenoviruses have high cytotoxicity and immunogenicity. Therefore, lentiviruses or adeno-associated viruses as viral vectors and herpes simplex virus as an oncolytic virus have recently drawn attention.

Nicotinamide Mononucleotide Is Safely Metabolized and Significantly Reduces Blood Triglyceride Levels in Healthy Individuals.

An increase in nicotinamide adenine dinucleotide (NAD) levels alleviates age-related disease progression and promotes healthy life expectancy. Several studies have demonstrated that NAD levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake; additionally, the safety of its oral ingestion has been confirmed in recent clinical trials. However, the efficacy and safety of intravenous NMN administration in humans remain unclear.

Effects of inhalable gene transfection as a novel gene therapy for non-small cell lung cancer and malignant pleural mesothelioma.

Gene therapy using vectors has attracted attention in recent years for the treatment of cancers caused by gene mutations. Besides, new treatments are imperative for lung cancer, including non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), due to its high mortality. We developed a minimally invasive and orally inhalable tumor suppressor gene drug (SFD-p16 and SFD-p53) with non-viral vectors for lung cancer treatment by combining tumor suppressor genes with an inhalant powder that can deliver active ingredients directly to the lung.

Triple-negative expression (ALDH1A1-/CD133-/mutant p53-) cases in lung adenocarcinoma had a good prognosis.

Cancer stem cells (CSCs) are major contributors to the malignant transformation of cells because of their capacity for self-renewal. Aldehyde dehydrogenase1A1 (ALDH1A1) and CD133 are promising candidate of CSC markers in non-small cell lung cancer (NSCLC). Furthermore, TP53 is frequently mutated in lung cancer, and the loss of its function is associated with malignant characteristics.

Cancer Cell-specific Transfection of hCas9 Gene Using Ad5F35 Vector.

Background: The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) is thought to have promising clinical potential. However, the off-target effects of Cas9 are a major concern for its application. Therefore, we hypothesized that the adverse effects of off-target gene editing might be minimized if the human codon-optimized Streptococcus pyogenes Cas9 (hCas9) could be specifically expressed in cancer cells.

Association Between CD133 Expression and Prognosis in Human Lung Adenocarcinoma.

Background/aim: CD133 is a promising candidate marker for cancer stem cells. However, clinical studies on CD133 expression in human lung adenocarcinoma have not yet been conducted. We hypothesized that CD133 expression in lung adenocarcinoma is a poor prognostic factor.

Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug.

We carried out structure-activity relationship study on anti-cancer effects of naftopidil (1) and its metabolites, resulted in identification of 1-(4-hydroxy-2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy) propan-2-ol (2, HUHS190), a major human metabolite of 1, which exhibited the most selective toxicities between against normal and cancer cells (Table 1). 2 was more hydrophilic compared to 1, was enough to be prepared in high concentration solution of more than 100 μM in saline for an intravesical instillation drug. Moreover, serum concentration of 2 was comparable to that of 1, an oral preparation drug, after oral administration at 32 mg/kg (Fig.

Lentiviral Vector-mediated Gene Transfer in Human Bladder Cancer Cell Lines.

Background/aim: Currently, treatment of non-muscle invasive bladder cancer causes significant deterioration in a patient's quality of life (QOL). Therefore, development of novel therapeutic options without the deterioration of QOL is very important. In this study, we assessed the anti-tumor effect of lentivirus-mediated gene transfection of tumor-suppressor genes in human bladder cancer cells.

Autophagy Induced by Naftopidil Inhibits Apoptosis of Human Gastric Cancer Cells.

Aim: Naftopidil is used to treat benign prostate hyperplasia. Moreover, previous studies have shown that naftopidil reduced viability of many types of cancer cells. Therefore, we investigated the antitumor mechanism of naftopidil in this study.

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma.

Background/aim: Aldehyde dehydrogenase-1A1 (ALDH1A1) and CD133 have been identified as markers of cancer stem cells (CSCs). We investigated the expression of these markers and their clinical significance in lung adenocarcinoma.

Materials And Methods: An immunohistochemical analysis of ALDH1A1 and CD133 expression of 92 lung adenocarcinomas was performed.

The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling.

Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation.

Piperazine-based Alpha-1 AR Blocker, Naftopidil, Selectively Suppresses Malignant Human Bladder Cells via Induction of Apoptosis.

A retrospective observational cohort study has shown that exposure to alpha-1 adrenergic receptor (AR) blocker reduces the risk of bladder cancer (BCa). We investigated the antitumor activity of alpha-1 blockers, that are administered long-term therapeutically, in BCa. The antitumor activity of alpha-1 blockers was evaluated in terms of cell viability, cell cycle, competition, and apoptotic signaling in BCa cells.

Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma.

Background/aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment.

Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA.

Naftopidil is useful for the treatment of malignant pleural mesothelioma.

Naftopidil, an α1-adrenoceptor blocker, induced apoptosis of human malignant pleural mesothelioma NCI-H2052 cells. Naftopidil upregulated the expression of tumor necrosis factor-α (TNF-α) mRNA in these cells. Naftopidil, alternatively, increased FasL secretion from NCI-H2052 cells, without affecting the expression of FasL mRNA and protein, and activated caspase-3 and -8 in NCI-H2052 cells.

Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma.

The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 μM. HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis.

Biosafety studies of carrier cells infected with a replication-competent adenovirus introduced by IAI.3B promoter.

The use of carrier cells infected with oncolytic viruses in cancer gene therapy is an attractive method because it can overcome viral immunogenicity and induce tumor immunity and significant antitumor activity. To enable human clinical trials of this treatment, acute and chronic toxicity tests must first be performed to ensure safety. IAI.

Crosstalk between PI3 kinase/PDK1/Akt/Rac1 and Ras/Raf/MEK/ERK pathways downstream PDGF receptor.

Background/aims: Our earlier studies suggested crosstalk between IRS/PI3 kinase/PDK1/Akt/Rac1/ROCK and (Shc2/Grb2/SOS)/Ras/Raf/MEK/ERK pathways downstream PDGF-ββ receptor responsible for chemotaxis and proliferation of malignant mesothelioma cells. The present study was conducted to obtain evidence for this.

Methods: To assess activation of Akt, MEK, and ERK, Western blotting was carried out on MSTO-211H malignant mesothelioma cells using antibodies against phospho-Thr308-Akt, phopho-Ser473-Akt, Akt, phospho-MEK, MEK, phopho-ERK1/2, and ERK1/2.

Naftopidil induces apoptosis in malignant mesothelioma cell lines independently of α1-adrenoceptor blocking.

Background: Naftopidil, an α1-adrenoceptor blocker, has been clinically used for the treatment of benign prostate hyperplasia and hypertension. Emerging evidence has shown that naftopidil exhibits an antitumor effect on a variety of cancer types including prostate cancer. The aim of the present study was to investigate naftopidil-induced apoptosis in human malignant mesothelioma cells and to shed light on the underlying mechanism.

Fiber-substituted conditionally replicating adenovirus Ad5F35 induces oncolysis of human bladder cancer cells in in vitro analysis.

Objective: To assess the oncolytic effect of fiber-substituted conditionally replicating adenovirus type 5 (Ad5) F35 vector on human bladder cancer cell lines such as 253J, 5637, KK-47, T24, TCCSUP, and UMUC-3 cells.

Materials And Methods: Ad5F35 and Ad5 conditionally replicating adenovirus vectors containing the E1 gene controlled by the human midkine promoter (Ad5F35/MKp-E1 and Ad5/MKp-E1, respectively) were constructed. Reverse transcriptase-polymerase chain reaction and cell viability assay were performed in cells transfected with Ad5F35/MKp-E1 or Ad5/MKp-E1.

Sphingosine suppresses mesothelioma cell proliferation by inhibiting PKC-δ and inducing cell cycle arrest at the G(0)/G(1) phase.

Background/aims: Sphingosine regulates cellular differentiation, cell growth, and apoptosis. The present study aimed at understanding sphingosine-regulated mesothelioma cell proliferation.

Methods: Human malignant mesothelioma cells such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells were cultured.

Sphingosine induces apoptosis in MKN-28 human gastric cancer cells in an SDK-dependent manner.

Background/aims: Evidence has pointed to the role of sphingosine in cellular differentiation, cell growth, and apoptosis. The present study investigated sphingosine-induced apoptosis in human gastric cancer cells.

Methods: Well differentiated MKN-28 and poorly differentiated MKN-45 human gastric cancer cells were cultured.

A3 adenosine receptor mediates apoptosis in in vitro RCC4-VHL human renal cancer cells by up-regulating AMID expression.

Purpose: Accumulating studies have shown that extracellular adenosine induces apoptosis in various cancer cells via diverse signaling pathways. We sought to understand adenosine induced apoptosis in human renal cancer cells and the underlying pathway.

Materials And Methods: RCC4-VHL (European Collection of Animal Cell Cultures, Salisbury, United Kingdom), ACHN (Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohuku University, Aoba-ku, Sendai, Japan) and 786-O (ATCC®) human renal cancer cells were cultured.

A(3) adenosine receptor mediates apoptosis in 5637 human bladder cancer cells by G(q) protein/PKC-dependent AIF upregulation.

Background/aims: A(3) adenosine receptor mediates apoptosis in a variety of cancer cells via diverse signaling pathways. The present study was conducted to assess A(3) adenosine receptor-mediated apoptosis in human bladder cancer cell lines and to understand the underlying mechanism.

Methods: Human bladder cancer cell lines such as 253J, 5637, KK-47, TCCSUP, T24, and UMUC-3 cells were cultured.

Beneficial oncolytic effect of fiber-substituted conditionally replicating adenovirus on human lung cancer.

Background: Adenovirus vectors have been utilized for a variety of cancer gene therapy. The present study examined the oncolytic effect of adenovirus type 5 (Ad5) and fiber-substituted conditionally replicating adenovirus (CRAD) Ad5/F35 vectors on human lung cancer A549 cells (an epithelial adenocarcinoma cell line), SBC-3 cells (a small-cell cancer cell line), and Lu-65 cells (a giant-cell lung cancer cell line).

Materials And Methods: For adenovirus, the first mRNA/protein to be made (~1 h after infection) is early region 1A (E1A).

Potential tumor markers of renal cell carcinoma: α-enolase for postoperative follow up, and galectin-1 and galectin-3 for primary detection.

The diagnosis of renal cell carcinoma is currently based on imaging techniques, mainly because there is no blood marker available for its detection. Thus, there is still the need for the development of novel tumor markers. We examined plasma levels of eight proteins in 15 renal cell carcinoma patients before and after surgery, and in 51 healthy controls using enzyme-linked immunosorbent assay.