Targeting Intracellular Calcium Signaling ([Ca]) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview.

Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance.

Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs).

Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression.

Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma.

Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.

MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM.

Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells.

Interferon-β Modulates the Innate Immune Response against Glioblastoma Initiating Cells.

Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-β might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC.

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts.

We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts' aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation.

miR-23a-3p causes cellular senescence by targeting hyaluronan synthase 2: possible implication for skin aging.

Even though aging and cellular senescence appear to be linked, the biological mechanisms interconnecting these two processes remain to be unravelled. Therefore, microRNA (miRNA/miR) profiles were analyzed ex vivo by means of gene array in fibroblasts isolated from young and old human donors. Expression of several miRNAs was positively correlated with donor age.

Cisplatin (CDDP) triggers cell death of MCF-7 cells following disruption of intracellular calcium ([Ca(2+)]i) homeostasis.

Breast cancer (BC) is a public health problem all over the world. Cisplatin (CDDP) is an antineoplastic agent with high rate of success in treating cancers. The down side of CDDP treatment is the development of chemo-resistance.

Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells.

Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O(6)-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation.

Thymosin β 4 gene silencing decreases stemness and invasiveness in glioblastoma.

Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. Thymosin beta 4 gene silencing promotes differentiation of neural stem cells whereas thymosin beta 4 overexpression initiates cortical folding of developing brain hemispheres. A role of thymosin beta 4 in malignant gliomas has not yet been investigated.

DNA methylation pyrosequencing assay is applicable for the assessment of epigenetic active environmental or clinical relevant chemicals.

Exposure of cells and organisms to stressors might result in epigenetic changes. Here it is shown that investigation of DNA methylation using pyrosequencing is an alternative for in vitro and in vivo toxicological testing of epigenetic effects induced by chemicals and drugs. An in vitro evaluation of global and CpG site specific DNA methylation upon treatment of cells with chemicals/drugs is shown.

Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells.

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma. Clinical benefit is more prominent in patients with methylation of the O(6) -methyl-guanine DNA methyltransferase (MGMT) promoter. However, all patients eventually suffer from tumor progression because their tumors become resistant to TMZ.

Metals and breast cancer: risk factors or healing agents?

Metals and metal compounds are part of our environment. Several metals are essential for physiological functions (e.g.

Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects.

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g.

Anti-cancer drugs interfere with intracellular calcium signaling.

(Neuro-)toxicity of metal and metal compounds is frequently highlighted. While specific metals or metal compounds are essential for cellular function, other metals are toxic and/or carcinogens. Metals can trigger accidental cell death in the form of necrosis, or activate programmed cell death in the form of apoptosis.

Binding of PDZ proteins to HPV E6 proteins does neither correlate with epidemiological risk classification nor with the immortalization of foreskin keratinocytes.

There is compelling evidence that high-risk human papillomaviruses (HPV) can cause cervical cancer. Strikingly, HPV16 and 18 account for approximately 70% of all cervical cancers, whereas phylogenetically related types are found at much lower frequencies. Most likely, differences in the activities of the viral E6 and E7 oncoproteins account for the in vivo carcinogenicity.

Co-application of arsenic trioxide (As2O3) and cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca2+]i) and cytotoxicity.

Arsenic trioxide (As(2)O(3)) and cisplatin (CDDP) are clinically relevant chemotherapeutics which modulate the intracellular calcium concentration ([Ca(2+)](i)) by different mechanisms: As(2)O(3) depletes intracellular calcium stores while CDDP triggers an influx of Ca(2+). We investigate whether co-application of As(2)O(3) and CDDP has an effect on [Ca(2+)](i) homeostasis, resulting in an increase of cytotoxicity/apoptosis in human SY-5Y neuroblastoma cells. Confocal imaging with Ca(2+)-sensitive dye (fluo-4) was used for investigating [Ca(2+)](i) dynamics.

Arsenic trioxide in environmentally and clinically relevant concentrations interacts with calcium homeostasis and induces cell type specific cell death in tumor and non-tumor cells.

While arsenic compounds are known as environmental toxicants (especially in drinking water) and as carcinogens, some arsenic compounds, like arsenic trioxide (As2O3), are clinically used in humans to treat some forms of cancer (e.g. leukemia).

Arsenic trioxide (As2O3) induced calcium signals and cytotoxicity in two human cell lines: SY-5Y neuroblastoma and 293 embryonic kidney (HEK).

Arsenic trioxide (As(2)O(3)) has anticancer properties; however, its use also leads to neuro-, hepato- or nephro-toxicity, and therefore, it is important to understand the mechanism of As(2)O(3) toxicity. We studied As(2)O(3) influence on intracellular calcium ([Ca(2+)](i)) homeostasis of human neuroblastoma SY-5Y and embryonic kidney cells (HEK 293). We also relate the As(2)O(3) induced [Ca(2+)](i) modifications with cytotoxicity.

Occurrence, use and potential toxic effects of metals and metal compounds.

Metals and metal compounds are constituents of our natural environment. Their distribution depends on the existence of natural sources (e.g.

Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3.

Physiological modifications of intracellular Ca2+ ([Ca2+]i) levels trigger and/or regulate a diversity of cellular activities (e.g. neurotransmitter release, synaptic plasticity, muscular contraction, cell proliferation), while calcium overloads could result in cytotoxicity.

Intracellular calcium disturbances induced by arsenic and its methylated derivatives in relation to genomic damage and apoptosis induction.

Arsenic and its methylated derivatives are contaminants of air, water, and food and are known as toxicants and carcinogens. Arsenic compounds are also being used as cancer chemotherapeutic agents. In humans, inorganic arsenic is metabolically methylated to mono-, di-, and trimethylated forms.

The delta e13 isoform of the calcitonin receptor forms a six-transmembrane domain receptor with dominant-negative effects on receptor surface expression and signaling.

The CTRdelta e13 splice variant of the rabbit calcitonin receptor, which lacks the 14 amino acids of the seventh transmembrane domain (TMD) that are encoded by exon 13, is poorly expressed on the cell surface, fails to mobilize intracellular calcium or activate Erk, and inhibits the cell surface expression of the full-length C1a isoform. Nuclear magnetic resonance- and fluorescence-activated cell sorter-based experiments showed that the residual seventh TMD of CTRdelta e13 fails to partition into the lipid bilayer, resulting in an extracellular C terminus. Truncating the receptor after residue 397 to delete the cytoplasmic tail resulted in reduced cell surface expression and an inability to mobilize intracellular calcium or activate Erk, but the truncated receptor did not inhibit C1a cell surface expression.

Elevated Ca2+(i) transients induced by trimethyltin chloride in HeLa cells: types and levels of response.

Humans are exposed to organotins, like trimethyltin (TMT) chloride via air, water and food, and intoxication might result in severe health complications. Toxic effects of organotin compounds are well documented, but possible mechanisms remain unclear and only little information is available how organometallic species interact with calcium controlling mechanisms. Therefore, the aim of this work was to investigate the effects of TMT on calcium homeostasis in HeLa S3 cells.