Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells.

BACKGROUND: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers. AIM: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents. METHODS: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays. RESULTS: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 µM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 µM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs. CONCLUSION: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.

Intranasal Lipid Particulate Drug Delivery Systems: An Update on Clinical Challenges and Biodistribution Studies of Cerebroactive Drugs in Alzheimer's disease.

BACKGROUND: Alzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities. OBJECTIVES: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs. METHOD: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data. RESULTS: From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes. CONCLUSION: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.

Differential Effects of Alzheimer's Disease Aß40 and 42 on Endocytosis and Intraneuronal Trafficking.

Anomalous neuronal accumulation of Aß peptides was shown to affect synaptic transmission and contribute to neurodegeneration in Alzheimer's disease (AD) brain. Neuronal cells internalize amyloid beta (Aß) peptides from the brain extracellular space even under normal physiological conditions, and these endocytotic pathways go awry during AD progression. We hypothesized that exposure to toxic Aß species accumulating in AD brain contributes to perturbations in neuronal endocytosis. We have shown substantial down-regulation of KEGG endocytotic pathway genes in AD patient brain regions that accumulate Aß compared to those in non-demented individuals. While both Aß40 and Aß42 perturbed endocytosis and intracellular trafficking in neuronal cells, Aß40 had a greater effect than Aß42. Moreover, Aß40 decreased the neuronal uptake and lysosomal accumulation of Aß42, which tends to oligomerize at low lysosomal pH. Hence, Aß40 may reduce the prevalence of stable Aß42 oligomers that are closely associated with neurodegeneration and are intercellularly propagated across the vulnerable brain regions to eventually nucleate as amyloid plaques. In conclusion, elevated brain Aß levels and Aß42:40 ratio apparent in the early stages of AD could perturb intraneuronal trafficking, augment the anomalous accumulation of amyloid peptides in AD brain, and drive AD pathogenesis.