A Short Post-Reattachment Ultrasensitive Window of Time in Human Cancer Cells as Therapeutic Target of Prolonged Low-Dose Administration of Specific Compounds.

Prolonged low-dose administration (PLDA) of several FDA-approved drugs for noncancer conditions or dietary compounds is associated with a lower incidence of specific types of cancers and with the lower formation of metastasis. However, the underlying mechanism is unknown; there is a discrepancy between the concentration of drugs needed to kill cancer cells in vitro and the actual serum levels (10 and >1000 times lower) found in patients. In this study, we evaluated the hypothesis that clonogenicity may be the target of PLDA.

Phenotypic Characterization of 2D and 3D Prostate Cancer Cell Systems Using Electrical Impedance Spectroscopy.

Prostate cancer is the second leading cause of death in men. A challenge in treating prostate cancer is overcoming cell plasticity, which links cell phenotype changes and chemoresistance. In this work, a microfluidic device coupled with electrical impedance spectroscopy (EIS), an electrode-based cell characterization technique, was used to study the electrical characteristics of phenotype changes for (1) prostate cancer cell lines (PC3, DU145, and LNCaP cells), (2) cells grown in 2D monolayer and 3D suspension cell culture conditions, and (3) cells in the presence (or absence) of the anti-cancer drug nigericin.

Two-Step Preparation of Protein-Decorated Biohybrid Quantum Dot Nanoparticles for Cellular Uptake.

Decoration of nanoparticles with specific molecules such as antibodies, peptides, and proteins that preserve their biological properties is essential for the recognition and internalization of their specific target cells. Inefficient preparation of such decorated nanoparticles leads to nonspecific interactions diverting them from their desired target. We report a simple two-step procedure for the preparation of biohybrid nanoparticles containing a core of hydrophobic quantum dots coated with a multilayer of human serum albumin.

Alternative models of cancer stem cells: The stemness phenotype model, 10 years later.

The classical cancer stem cell (CSCs) theory proposed the existence of a rare but constant subpopulation of CSCs. In this model cancer cells are organized hierarchically and are responsible for tumor resistance and tumor relapse. Thus, eliminating CSCs will eventually lead to cure of cancer.

One Step Histological Detection and Staining of the PTEN Tumor Suppressor Protein by a Single Strand DNA.

Antibodies are the most used technological tool in histochemistry. However, even with monoclonal antibodies, their standardization is difficult due to variation of biological systems as well as to variability due to the affinity and amplification of the signal arising from secondary peroxidase detection systems. In this article we combined two synthetic molecules to facilitate the standardization of a detection protocol of protein markers in histological sections.

The Biguanides Metformin and Buformin in Combination with 2-Deoxy-glucose or WZB-117 Inhibit the Viability of Highly Resistant Human Lung Cancer Cells.

The biguanides metformin (MET) and to a lesser extent buformin (BUF) have recently been shown to exert anticancer effects. In particular, MET targets cancer stem cells (CSCs) in a variety of cancer types but these compounds have not been extensively tested for combination therapy. In this study, we investigated the anticancer activity of MET and BUF alone or in combination with 2-deoxy-D-glucose (2-DG) and WZB-117 (WZB), which are a glycolysis and a GLUT-1 inhibitor, respectively, in H460 human lung cancer cells growing under three different culture conditions with varying degrees of stemness: (1) routine culture conditions (RCCs), (2) floating lung tumorspheres (LTSs) that are enriched for stem-like cancer cells, and (3) adherent cells under prolonged periods (8-12 days) of serum starvation (PPSS).

Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers.

Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have demonstrated potent anticancer activities against cancer stem-like cells that are considered highly resistant to chemotherapy and responsible for tumor relapse.

Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib.

The presence of highly resistant cancer cells and the toxicity to normal cells are key factors that limit chemotherapy. Here, we used two models of highly resistant lung cancer cells: (1) adherent cells growing under prolonged periods of serum starvation (PPSS) and (2) cells growing as floating tumorspheres (FTs) to evaluate the effect of Verapamil (VP) in combination with Sorafenib (SF). Compared to cells growing under routine culture conditions (RCCs), PPPS cells or FTs were highly sensitive to short-term exposure (24 h) to VP 100 M + SF 5 M (VP100 + SF5).

Translational gap in ongoing clinical trials for glioma.

Despite the vast amounts of information gathered about gliomas, the overall survival of glioma patients has not improved in the last four decades. This could partially be due to an apparent failure to include basic concepts of glioma biology into clinical trials. Specifically, attempts to overcome the limitations of the blood brain barrier (BBB) and the chemoresistance of glioma stem cells (GSCs) were seldom included (a phenomenon known as the translational gap, TG) in a study involving 29 Phase I/II clinical trials (P2CT) published in 2011.

Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides.

Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation.

Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers.

Breast cancer is second most prevalent cancer in women, and the second only to lung cancer in cancer-related deaths. It is a heterogeneous disease and has several subtypes based on the presence or absence of hormone receptors and/or human epidermal growth factor receptor 2 (HER2). Hormone receptor-positive and HER2-enriched cancers can be targeted using hormone and HER2-targeting therapies such as trastuzumab or lapatinib.

Cancer Cell Plasticity: Rapid Reversal of Chemosensitivity and Expression of Stemness Markers in Lung and Breast Cancer Tumorspheres.

In cancer cells, the reversible nature of the stemness status in terms of chemoresistance has been poorly characterized. In this study, we have simulated one cycle of environmental conditions to study such reversibility by first generating floating tumorspheres (FTs) from lung and breast cancer cells by culturing them in serum-free media without the addition of any external mitogenic stimulation, and subsequently (after 2 weeks) re-incubating them back in serum-containing media to simulate routine culture conditions (RCCs). We found that cancer cells are extremely plastic: cells grown under RCCs become multidrug-resistant when grown as FTs, but upon re-incubation under RCCs quickly re-attach and lose the acquired resistance.

Anti-Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres.

Lung cancer is a leading cause of cancer-related death in the United States. Although several drugs have been developed that target individual biomarkers, their success has been limited due to intrinsic or acquired resistance for the specific targets of such drugs. A more effective approach is to target multiple pathways that dictate cancer progression.

Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation.

The efficacy of chemotherapy is hindered by both tumor heterogeneity and acquired or intrinsic multi-drug resistance caused by the contribution of multidrug resistance proteins and stemness-associated prosurvival markers. Therefore, targeting multi-drug resistant cells would be much more effective against cancer. In this study, we characterized the chemoresistance properties of adherent (anchorage-dependent) lung H460 and breast MCF-7 cancer cells growing under prolonged periods of serum starvation (PPSS).

Formation of Tumorspheres with Increased Stemness without External Mitogens in a Lung Cancer Model.

Like with most solid tumors, the presence of a subpopulation of cancer stem cells (CSCs) or cancer stem-like cells (CS-LCs) has been associated with chemoresistance and tumor relapse in lung cancer cells. In the absence of serum, CSCs/CS-LCs have the ability to grow as lung tumorspheres (LTSs), and this system is routinely used for isolation and characterization of putative CSCs/CS-LCs. Methods to isolate LTSs are usually performed in serum-free media supplemented with specific additives such as epidermal growth factor and basic fibroblast growth factor.

Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel.

Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor.

Translational gap in glioma research.

During the last five decades, enormous advances in treatment modalities for cancer and a better understanding of cancer cell biology have been accomplished but the prognosis of patients carrying malignant gliomas still remains poor despite hundreds of clinical trials have been carried out. In this article we review phase II clinical trials that have been completed and published in PubMed during 2011 in order to investigate potential reasons of clinical failure. We suggest that a translational gap, defined as a failure to translate basic research into clinical trials design may explain the poor outcome of phase II clinical trials.

Stemness and plasticity of lung cancer cells: paving the road for better therapy.

Lung cancer is a devastating disease that is responsible for around 160,000 deaths each year in United States. The discovery that lung cancer, like most other solid tumors, contains a subpopulation of cancer stem cells or cancer stem-like cells (CSCs/CS-LCs) that if eliminated could lead to a cure has brought new hope. However, the exact nature of the putative lung CSCs/CS-LCs is not known and therefore therapies to eliminate this subpopulation have been elusive.

System models, assays and endpoint parameters to evaluate anticancer compounds during preclinical screening.

The effectiveness of anticancer therapies relies on the ability of these substances to selectively eliminate the malignant cells with little or no toxicity to normal cells. The isolation in most human tumors of a rare subpopulation of cancer stem cells (CSCs) associated with chemo resistance leads to the "stem cell theory" (SCT). The SCT proposed that eliminating this fraction will eventually cure cancer but experimental data supporting this classical view are controversial and now being gradually replaced by other models.

Natural products targeting autophagy via the PI3K/Akt/mTOR pathway as anticancer agents.

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is a key regulator of authophagy. Natural products show anticancer activity and often induce apoptosis or autophagy. The crosstalk between these two types of cell death makes autophagy an interesting target since drugs targeting this process not only can induce cell death by inducing autophagy but can also sensitize cells to apoptosis.

Overcoming the blood-brain barrier for chemotherapy: limitations, challenges and rising problems.

Treatment of brain tumors with chemotherapy is limited mostly because of delivery impediments related to the blood-brain barrier (BBB). For gliomas, the most common and aggressive primary brain tumor, treatment includes surgery, radiotherapy, and chemotherapy usually administered orally or intravenously. These routes do not deliver effective concentrations.

An Algorithm for the Preclinical Screening of Anticancer Drugs Effective against Brain Tumors.

The anticancer drugs screening program is a long and expensive process. It is estimated that only 5% of drugs entering clinical trials are approved by the FDA. Moreover, many of the drugs that enter clinical trials are often of limited use in clinical practice, and most cancers remain untreatable.

In vitro inhibition of topoisomerase IIα by reduced glutathione.

In most cells, the major intracellular redox buffer is glutathione (GSH) and its disulfide-oxidized (GSSG) form. The GSH/GSSG system maintains the intracellular redox balance and the essential thiol status of proteins by thiol disulfide exchange. Topoisomerases are thiol proteins and are a target of thiol-reactive substances.

Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells.

Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.