Newly synthesized acridone derivatives targeting lung cancer: A toxicity and xenograft model study.

AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (AC-2, AC-7, and AC-26) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated AC-2 to be inhibiting HOP-62 induced tumor via reduction in p-AKT1 (Ser473) expression significantly. In immunofluorescence staining AC-2 treated tissue section showed 2.5 fold reduction in the expression of p-AKT1 (Ser473). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that AC-2 causes cell necrosis in tumor cells via blocking the p-AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.

Transition metal complexes of a multidentate Schiff base ligand containing pyridine: synthesis, characterization, enzyme inhibitions, antioxidant properties, and molecular docking studies.

A series of Fe(II), Ni(II), and Pd(II) complexes were prepared with a novel Schiff base ligand containing pyridine moiety. The prepared compounds were characterized using FT-IR, 1H and 13 C NMR, UV-Vis, powder XRD, thermogravimetric analysis, mass spectra, magnetic susceptibility, and elemental analysis. The coordination geometry of Fe(II) and Ni(II) complexes were octahedral, where Fe(II) and Ni(II) metal ions were coordinated by an oxygen atom of the carbonyl group, a nitrogen atom of the azomethine moiety, and a phenolic oxygen atom. The Pd(II) complex had square planar geometry. All of the synthesized compounds were tested for their biochemical properties, including enzyme inhibition and antioxidant activities. According to the in vitro DPPH and FRAP antioxidant methods, the Schiff base ligand and its Fe(II)/Pd(II) complexes showed close antioxidant activities against the standards (BHA, BHT, ascorbic acid, and α-tocopherol). Enzyme inhibitions of the metal complexes were investigated against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The best inhibition value (Ki) was observed for the Ni(II) complex against GST (2.63 ± 0.04 µM). Also, the Pd(II) complex showed the best inhibition value (10.17 ± 1.88 µM) against AChE. Molecular docking specified significant interactions at the active pockets of respective target enzymes. The Ni(II) complex exhibited good binding affinity against both BChE (- 9.0 kcal/mol and 9.36 ± 2.03 µM) and GST (- 7.0 kcal/mol and 2.63 ± 0.04 µM) enzymes.

Current Developments in Targeted Drug Delivery Systems for Glioma.

BACKGROUND: Glioma is one of the most commonly observed tumours, representing about 75% of brain tumours in the adult population. Generally, glioma treatment includes surgical resection followed by radiotherapy and chemotherapy. The current chemotherapy for glioma involves the use of temozolomide, doxorubicin, monoclonal antibodies, etc. however, the clinical outcomes in patients are not satisfactory. Primarily, the blood-brain barrier hinders these drugs from reaching the target leading to the recurrence of glioma post-surgery. In addition, these drugs are not target-specific and affect the healthy cells of the body. Therefore, glioma-targeted drug delivery is essential to reduce the rate of recurrence and treat the condition with more reliable alternatives. METHODS: A literature search was conducted to understand glioma pathophysiology, its current therapeutic approaches for targeted delivery using databases like Pub Med, Web of Science, Scopus, and Google Scholar, etc. Results: This review gives an insight to challenges associated with current treatments, factors influencing drug delivery in glioma, and recent advancements in targeted drug delivery. CONCLUSION: The promising results could be seen with nanotechnology-based approaches, like polymeric, lipidbased, and hybrid nanoparticles in the treatment of glioma. Biotechnological developments, such as carrier peptides and gene therapy, are future prospects in glioma therapy. Therefore, these targeted delivery systems will be beneficial in clinical practices for glioma treatment.

Combination Therapies of Artemisinin and its Derivatives as a Viable Approach for Future Cancer Treatment.

BACKGROUND: Many anticancer drugs have been developed for clinical usage till now, but the major problem is the development of drug-resistance over a period of time in the treatment of cancer. Anticancer drugs produce huge adverse effects, ultimately leading to death of the patient. Researchers have been focusing on the development of novel molecules with higher efficacy and lower toxicity; the anti-malarial drug artemisinin and its derivatives have exhibited cytotoxic effects. METHODS: We have done extensive literature search for artemisinin for its new role as anti-cancer agent for future treatment. Last two decades papers were referred for deep understanding to strengthen its role. RESULT: Literature shows changes at 9, 10 position in the artemisinin structure produces anticancer activity. Artemisinin shows anticancer activity in leukemia, hepatocellular carcinoma, colorectal and breast cancer cell lines. Artemisinin and its derivatives have been studied as combination therapy with several synthetic compounds, RNA interfaces, recombinant proteins and antibodies etc., for synergizing the effect of these drugs. They produce an anticancer effect by causing cell cycle arrest, regulating signaling in apoptosis, angiogenesis and cytotoxicity activity on the steroid receptors. Many novel formulations of artemisinin are being developed in the form of carbon nanotubes, polymer-coated drug particles, etc., for delivering artemisinin, since it has poor water/ oil solubility and is chemically unstable. CONCLUSION: We have summarize the combination therapies of artemisinin and its derivatives with other anticancer drugs and also focussed on recent developments of different drug delivery systems in the last 10 years. Various reports and clinical trials of artemisinin type drugs indicated selective cytotoxicity along with minimal toxicity thus projecting them as promising anti-cancer agents in future cancer therapies.

Tumor Microenvironment Targeted Nanotherapy.

Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect promotes nano-chemotherapeutics extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of nano-chemotherapeutics and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of nano-chemotherapeutics in non-tumor-stroma cells damages the non-tumor cells, and interferes with tumor-stroma crosstalk. This can lead not only to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a vital role in regulating nano-chemotherapeutics distribution and their biological effects. In this review, the barriers in tumor microenvironment, its consequential effects on nano-chemotherapeutics, considerations to improve nano-chemotherapeutics delivery and combinatory strategies to overcome acquired resistance induced by tumor microenvironment have been summarized. The various strategies viz., nanotechnology based approach as well as ligand-mediated, redox-responsive, and enzyme-mediated based combinatorial nanoapproaches have been discussed in this review.

Drug-DNA Interaction Studies of Acridone-Based Derivatives.

N10-alkylated 2-bromoacridones are a novel series of potent antitumor compounds. DNA binding studies of these compounds were carried out using spectrophotometric titrations, Circular dichroism (CD) measurements using Calf Thymus DNA (CT DNA). The binding constants were identified at a range of K=0.3 to 3.9×10(5) M(-1) and the percentage of hypochromism from the spectral titrations at 28-54%. This study has identified a compound 9 with the good binding affinity of K=0.39768×10(5) M(-1) with CT DNA. Molecular dynamics (MD) simulations have investigated the changes in structural and dynamic features of native DNA on binding to the active compound 9. All the synthesized compounds have increased the uptake of Vinblastine in MDR KBChR-8-5 cells to an extent of 1.25- to1.9-fold than standard modulator Verapamil of similar concentration. These findings allowed us to draw preliminary conclusions about the structural features of 2-bromoacridones and further chemical enhancement will improve the binding affinity of the acridone derivatives to CT-DNA for better drug-DNA interaction. The molecular modeling studies have shown mechanism of action and the binding modes of the acridones to DNA.

Nanodrug delivery in reversing multidrug resistance in cancer cells.

Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. "Theragnostics" combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell.

Identification and usage of fluorescent probes as nanoparticle contrast agents in detecting cancer.

As advancements in the field of nanoparticle imaging science are made, one of the first benefits will be in open and endoscopic conditions. There is considerable evidence indicating that the use of injected contrast agents can improve the detection of tumor margins and small metastases. New and innovative targeting and contrast agents including small molecules, antibodies and nanoparticles have to be developed for a broad range of tumor types such as breast, brain, pancreatic, and ovarian cancers. At present, a number of organic dye molecules have been approved for human use including (1) indocyanine green (ICG), a near-infrared fluorescent dye; (2) fluorescein, a green fluorescent dye; (3) photofrin, a mixture of fluorescent protoporphyrin oligomers approved for photodynamic therapy, and (4) 5-aminolevulinic acid (ALA), a small molecule that is preferentially taken up by tumor cells leading to biosynthesis and accumulation of protoporphyrin IX, a natural fluorophore with red fluorescence emission. On the other hand, nanoparticles have not received FDA approval for clinical imaging, as this technology needs a lot of development and lot of research is being carried out in this unexplored area. A major task is, therefore to develop biocompatible and nontoxic nanoparticle contrast agents with the potential for FDA approval and human use. Such agents need to show improved sensitivity and specificity for tumor imaging in comparison with small-molecule-dyes. In this regard, it is highly promising to develop smart or activatable nanoparticles with improved pharmacokinetic, tumor targeting and organ clearance properties, based on the use of natural, biodegradable polymers (dextran and heparin). Dextran-based particles are sensitive to pH, and can be rapidly broken down under acidic conditions. Under neutral or slightly basic conditions, on the other hand, the dextran nanoparticles are stable and are able to circulate systemically in blood for 14 to 15 hours. In contrast, self-assembled heparin nanoparticles have much shorter blood circulation half-lives (about 60-80 min). For intra-operative use, this short circulation time could be beneficial because the probes will be cleared from the body quickly, so that surgical operations and treatment can start without much delay or waiting. For near-term clinical applications, it is important that both the dextran and heparin particles are able to trap as FDA-approved dye (such as indocyanine green), leading to new class of imaging contrast agents with improved bio distribution and photo physical properties. This class of nanoparticle contrast agents could also be conjugated with tumor targeting ligands such as folate, Epidermal Growth Factor (EGF), or RGD (recognition sequence for integrins that contains Arg-Gly-Asp attachment site) for improved sensitivity and specificity in perfect cancer imaging technique agents. This review article actually highlights the new developments occurring in this area of imaging techniques in cancer research and the author himself is using the technique for developing newer fluorescent molecules for molecular imaging using nanotechnology.

Synthesis and in vitro cytotoxicity studies of certain novel heterocycles derived from bis 1, 2, 4-triazoles and their DNA damage studies.

Synthesis and evaluation of cytotoxicity of a series of heterocyclic compounds derived from 1, 4-bis-(5- [hydrazinocarbonylmethylthio]-4-phenyl-1,2,4-triazol-3-yl) butane (1a-b) are described. The triazolo-triazoles (9-15) and thiadiazoles (16-18) were prepared from respective thiosemicarbazide intermediates (2-8). The Schiff bases (19-24) were prepared from (1a, b) by reacting with different carboxaldehydes in acetic acid medium. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The compounds were evaluated for in vitro cytotoxicity potential using the standard MTT assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29 and Breast Cancer MDA MB-231. The DNA damage activity of the compound 24 was evaluated by alkaline comet assay.