Drugs for the treatment of Alzheimer’s disease (AD) are in urgent demand due to the unmet need and the social burden associated with the disease. Curcumin has been historically considered as a beneficial product for anti-aging and AD. However, many efforts to develop curcumin for clinical use are hindered mainly due to its poor bioavailability. Recent development in drug delivery and structural design has resolved these issues. In this study, we identified a small molecule, TML-6, as a potential drug candidate for AD through screening a panel of curcumin derivatives using six biomarker platforms related to aging biology and AD pathogenesis. The structural modification of TML-6 is designed to improve the stability and metabolism of curcumin. Cell biological studies demonstrated that TML-6 could inhibit the synthesis of the β-amyloid precursor protein and β-amyloid (Aβ), upregulate Apo E, suppress NF-κB and mTOR, and increase the activity of the anti-oxidative Nrf2 gene. In the 3x-Tg AD animal model, TML-6 treatment resulted in significant improvement in learning, suppression of the microglial activation marker Iba-1, and reduction in Aβ in the brain. Although TML-6 exhibited a greater improvement in bioavailability as compared to curcumin, formulation optimization and toxicological studies are under development to assure its druggability. Taken together, TML-6 meets the current strategy to develop therapeutics for AD, targeting the combination of the Aβ cascade and aging-related biology processes.

Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases.

Lutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis. Five human bladder cancer (E6, RT4, TSGH8301, TCCSUP and J82), one stable mouse fibroblast cell line (NIH-Lu) expressing Lu/BCAM transgene and sixty human uroepithelial carcinoma specimens were analyzed by real-time PCR, immunohistochemistry (IHC), immunofluorescence (IFA) staining, Western blotting and promoter luciferase assay for Lu/BCAM, respectively. The tumorigenicity of Lu/BCAM was demonstrated by focus formation, colony-forming ability, tumour formation, cell adhesion and migration. H-ras V12 was revealed to up-regulate Lu/BCAM at both transcriptional and translation levels. Lu/BCAM expression was detected on the membrane of primary human bladder cancer cells. Over-expression of Lu/BCAM in NIH-Lu stable cells increased focus number, colony formation and cell adhesion accompanied with F-actin rearrangement and decreased cell migration compared with parental NIH3T3 fibroblasts. In the presence of laminin ligand, Lu/BCAM overexpression further suppressed cell migration accompanied with increased cell adhesion. We further revealed that laminin-Lu/BCAM-induced cell adhesion and F-actin rearrangement were through increased Erk phosphorylation with an increase of RhoA and a decrease of Rac1 activity. Similarly, high Lu/BCAM expression was detected in the tumors of human renal pelvis, ureter and bladder, and was significantly associated with advanced tumor stage (p = 0.02). Patients with high Lu/BCAM expression showed a trend toward larger tumor size (p = 0.07) and lower disease-specific survival (p = 0.08), although not reaching statistical significance. This is the first report showing that Lu/BCAM, in the presence of its ligand laminin, is oncogenic in human urothelial cancers and may have potential as a novel therapeutic target.

Polyamidoamine (PAMAM) dendrimers are promising nonviral gene vectors due to their well-defined molecular structure, low immune response and ease of modification. High generation PAMAM dendrimers are reported with relatively high efficacy in the delivery of small interfering RNA (siRNA), but are suffering from several drawbacks such as severe cytotoxicity and high cost of manufacturing. Here, we report several efficient siRNA vectors based on low generation dendrimers. Dodecylated G2, G3 and G4 PAMAM dendrimers show dramatically increased gene silencing efficiency with negligible cytotoxicity on several cell lines compared to unmodified dendrimers. The increased gene silencing efficacy is mainly attributed to the hydrophobic modification on the dendrimer surface which significantly increases the cellular uptake of dendrimer/siRNA complexes. In addition, the most efficient polymer G4-23C12 can also efficiently deliver Bcl-2 siRNA into cancer cells, specifically inhibit the expression of target gene in vitro, and further lead to cell apoptosis. This study reveals the structure–function relationship of lipid-modified dendrimers in siRNA delivery and provides valuable insight to guide the development of efficient and non-toxic siRNA vectors.

For a number of years, oral cancer has remained in the top ten most common types of cancer, with an incidence rate that is steadily increasing. In total, ~75% oral cancer cases are associated with lifestyle factors, including uncontrolled alcohol consumption, betel and tobacco chewing, and the excessive use of tobacco. Notably, betel chewing is highly associated with oral cancer in Southeast Asia. Arsenic is a key environmental toxicant; however, arsenic trioxide has been used as a medicine for the treatment of acute promyelocytic leukemia, highlighting its anticancer properties. The present study aimed to investigate the role of arsenic compounds in the treatment of cancer, using FaDu oral squamous carcinoma cells treated with sodium arsenite (NaAsO₂) and dimethyl arsenic acid (DMA). The results demonstrated that FaDu cells exhibited membrane blebbing phenomena and high levels of apoptosis following treatment with 10 µM NaAsO₂ and 1 mM DMA for 24 h. The results of cell viability assay demonstrated that the rate of FaDu cell survival was markedly reduced as the concentration of arsenic compounds increased from 10 to 100 µM NaAsO₂, and 1 to 100 mM DMA. Moreover, flow cytometry was carried out to further examine the effects of arsenic compounds on FaDu cell cycle regulation; the results revealed that treatment with NaAsO₂ and DMA led to a significant increase in the percentage of FaDu cells in the sub‑G1 and G2/M phases of the cell cycle. An Annexin V/PI double staining assay was subsequently performed to verify the levels of FaDu cell apoptosis following treatment with arsenic compounds. Furthermore, the results of the western blot analyses revealed that the expression levels of caspase‑8, ‑9 and ‑3, and poly ADP‑ribose polymerase, as well the levels of phosphorylated JNK and ERK1/2 were increased following treatment with NaAsO₂ and DMA in the FaDu cells. On the whole, the results of the present study revealed that treatment with NaAsO₂ and DMA promoted the apoptosis of FaDu oral cancer cells, by activating MAPK pathways, as well as the extrinsic and intrinsic apoptotic pathways.