Cancer involves so rarely the eye that it may be recognized late. The most frequent primary intra-ocular tumours are retinoblastoma in small children and uveal melanoma in adults. Vision loss in systemic cancer has a varied differential diagnosis. Uveal metastases are most often associated with breast cancer, but can herald lung carcinoma. Masquerade syndrome looks like inflammation but represents the ocular involvement of primary CNS non-Hodgkin lymphoma. Systemic cancer drugs, as well as radiotherapy, can cause ocular toxicity, mostly at the retina. In the rare paraneoplastic syndromes, patient's cancer antibodies cross-react with retinal antigens, leading to severe vision loss. When cancer involves the eye, a fast referral into specialized care can significantly improve visual and vital prognosis.

Therapeutic touch (TT) is independent nursing intervention which is effective on nausea induced by chemotherapy but technique, steps and variables affected by this therapy are not yet well known. The aim of this study was to elicit descriptions of how TT is used with cancer patients, providing a basis for the systematic use and evaluation of TT with patients.

To observe the retinal vascular development and changes on aggressive posterior retinopathy of prematurity (AP-ROP) by intravitreal ranibizumab, evaluate the therapeutic effect, and provide the basis for clinical treatment.

Gold alkynyl complexes with phosphane ligands of the type (alkynyl)Au(I)(phosphane) represent a group of bioorganometallics, which has only recently been evaluated biologically in more detail. Structure-activity-relationship studies regarding the residues of the phosphane ligand (P(Ph)3, P(2-furyl)3, P(DAPTA)3, P(PTA)3, P(Et)3, P(Me)3) of complexes with an 4-ethynylanisole alkyne ligand revealed no strong differences concerning cytotoxicity. However, a relevant preference for the heteroatom free alkyl/aryl residues concerning inhibition of the target enzyme thioredoxin reductase was evident. Complex 1 with the triphenylphosphane ligand was selected for further studies, in which clear effects on cell morphology were monitored by time-lapse microscopy. Effects on cellular signaling were determined by ELISA microarrays and showed a significant induction of the phosphorylation of ERK1 (extracellular signal related kinase 1), ERK2 and HSP27 (heat shock protein 27) in HT-29 cells. Application of 1 in-vivo in a mouse xenograft model was found to be challenging due to the low solubility of the complex and required a formulation strategy based on a peanut oil nanoemulsion.

Since the prognosis for visual acuity after polychemotherapy or superselective intra-arterial chemotherapy (SIACT) is doubtful, studying retinal function in children with retinoblastoma by means of clinical electroretinography (ERG) is a relevant issue. The latter enables objective post-treatment assessment of retinal function and evaluation of possible infusion-related retinal toxicity. This review analyzes ERG findings in children with retinoblastoma treated with chemotherapy, including SIACT.

It was studied the effect of doxorubicin on the HIF system and the pro-antioxidant balance of neonatal cardiomyocytes as well as the possibility of the oxidative stress correcting using curcumin. It has been revealed that the expression of mRNA HIF-1α using doxorubicin at a dose of 0.5 μM was 2.9 ± 0.8 cu, so it decreased by 20% compared to control--3.6 ± 0.7 cu (P < 0.05). The level of expression of the HIF target gene PDK-1 also significantly decreased (4 times). During the incubation with doxorubicin, the number of live cells decreased by 50.4% relative to control. And after using doxorubicin and curcumin together, the percentage of dead cells decreased by 7,7 compared to doxorubicin only. Doxorubicin intoxication led to a significant increase in the secondary products of lipid peroxidation (TBARS) in cardiomyocytes by 3.6 times and hydrogen peroxide by 64%. Prolonged incubation with doxorubicin reduced the enzymatic activity of Mn-SOD by 32%, while catalase activity increased by 72% compared to control. Adding of curcumin to the cardiomyocyte cell culture contributed to increasing of the Mn-SOD activity by 14%, catalase--by 23%. The level of TBARS increased by 1,4 times compared with the control, and the level of H2O2 increased by 20%. The joint use of doxorubicin and curcumin resulted in a significant reduction of free radical oxidation unlike effect of doxorubicin per se. Specifically, there was lessening of TBARS and H2O2 (at 56.7 and 18.4% respectively), while decreasing of the catalase hyperactivation (19%) and rising of the Mn-SOD activity (35%).

Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity.

The p38 MAP kinase is a promising cancer drug target but its therapeutic effect is not fully understood. Here we report that the response of colorectal cancer (CRC) to p38 inhibitors (p38i) is highly variable: while p38i induces regression of one subgroup of CRCs, it stimulates growth of another subgroup. We further show that PP2AC is differentially expressed in the two different CRC subgroups, which determines the programing of p38-TSC-mTORC1 signaling through differential TSC2 phosphorylation at S664, 1254 and 1798, and the antitumor activity by p38i. Remarkably, modulation of PP2AC level is sufficient to reprogram p38-to-mTORC1 signaling and antitumor response. PP2AC expression accurately predicts therapeutic response to p38i in several CRC models, including a large cohort of patient-derived xenografts (PDXs). Moreover, we demonstrate that combination of p38 and mTOR kinase inhibitors effectively overcomes resistance to either inhibitor in single agent therapy. These results demonstrate that alternative routing of signal transduction underlies differential response to p38 and mTOR targeted therapies. The biomarker-guided therapeutic strategies described herein provide a compelling reason for testing in metastatic CRC patients who suffer very poor prognosis due to lack of efficacious drug therapies.

Medicinal plant extracts have been widely used for cancer treatment. Gaillardin is a natural sesquiterpene lactone that has recently been reported to have anticancer properties. The ability to induce apoptosis is an important property of a candidate anticancer drug, which discriminates between anticancer drugs and toxic compounds. The current study was therefore carried out to address the issue if Gaillardin is able to induce apoptosis in the breast cancer cell lines MCF-7 and MDA-MB-468 and to determine the underlying mechanism of its anticancer effects. Apoptosis induction by Gaillardin treatment was confirmed by annexin V-FITC/PI staining, and caspase-3,-6, and-9 activation. Using Western blot analysis, we found that Gaillardin upregulated the pro-apoptotic protein Bax and p53 and downregulated the anti-apoptotic protein Bcl-2. Moreover, the apoptotic effect of Gaillardin was also related to ROS production and loss of mitochondrial membrane potential (ΔΨm). Taken together, these results demonstrate that Gaillardin can inhibit proliferation of breast cancer cells via inducing mitochondrial apoptotic pathway and therefore, might be a promising molecule in cancer chemoprevention or chemotherapy.

Small molecules that bind genomic DNA have proven that they can be effective anticancer, antibiotic and antiviral therapeutic agents that affect the well-being of millions of people worldwide. Drug-DNA interaction affects DNA replication and division; causes strand breaks, and mutations. Therefore, the investigation of drug-DNA interaction is needed to understand the mechanism of drug action as well as in designing DNA-targeted drugs. On the other hand, the interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. For this purpose, electrochemical methods/biosensors can be used toward detection of drug-DNA interactions. The present paper reviews the drug-DNA interactions, their types and applications of electrochemical techniques used to study interactions between DNA and drugs or small ligand molecules that are potentially of pharmaceutical interest. The results are used to determine drug binding sites and sequence preference, as well as conformational changes due to drug-DNA interactions. Also, the intention of this review is to give an overview of the present state of the drug-DNA interaction cognition. The applications of electrochemical techniques for investigation of drug-DNA interaction were reviewed and we have discussed the type of qualitative or quantitative information that can be obtained from the use of each technique.

To investigate the anticancer effects of ring C in 18β-glycyrrhetinic acid (GA), a series of GA derivatives featured with 9(11)-ene moiety in ring C were designed and synthesized. The structures were confirmed by IR, LC-MS and 1H NMR. Their inhibitory effects towards human prostate cancer PC-3 and leukemia HL-60 cell lines were determined. Most of the derivatives displayed stronger antiproliferative activities than GA. Particularly, compound 14 showed promising anticancer activity with the GI50 values of 4.48 µmol · L(-1) and 1.2 µmol · L(-1) against PC-3 and HL-60 cells respectively, which is worth further study.

To discover an efficient strategy for the conversion of the antibacterial activity of fluoroquinolones into the antitumor activity, the three series of C-3 s-triazole-based derivatives including sulfide ketones (6a-6g), thiosemicarbazones (7a-7g) and fused heterocyclic thiazolotriazoles (8a-8g) were synthesized from ciprofloxacin (1), respectively. The structures were characterized by elemental analysis and spectral data. The antitumor activity was tested against three tumor cell lines (Hep-3B, Capan-1 and HL60) using the MTT assay. The three types of compounds all exhibited stronger anti-proliferative activities than ciprofloxacin in the test. The order of their activities was in compounds 7>8>6, and the order of selectivity against cancer cell lines was Capan-1, Hep-3B and HL60. Meanwhile, the SAR revealed that some compounds with electron-drawing group substituted such as fluoro- and nitro-phenyl compounds (6f, 7f, 8f) and (6g, 7g, 8g) displayed more significant activity than the control compounds, especially the IC50 values of thiosemicarbazone compounds 7f and 7g against Capan-1 was comparable to doxorubicin. Thus, a five-membered triazole as the C-3 bioisostere modified with the functionalized side-chain of sulfide-ketone thiosemicarbazone warrants special attention and further investigation.

The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the adjuvant treatment of non-small cell lung cancer (NSCLC) has not been well-established. Our meta-analysis aimed to determine whether the administration of EGFR-TKIs could improve the outcomes of patients with NSCLC undergoing complete resection.

High-grade serous ovarian cancer (HGSOC) has the highest mortality rate among all gynecological cancers. Patients are generally diagnosed in an advanced stage with the majority of cases displaying platinum resistant relapses. Recent genomic interrogation of large numbers of HGSOC patient samples indicated high complexity in terms of genetic aberrations, intra- and intertumor heterogeneity and underscored their lack of targetable oncogenic mutations. Sub-classifications of HGSOC based on expression profiles, termed 'differentiated', 'immunoreactive', 'mesenchymal' and 'proliferative', were shown to have prognostic value. In addition, in almost half of all HGSOC patients, a deficiency in homologous recombination (HR) was found that potentially can be targeted using PARP inhibitors. Developing precision medicine requires advanced experimental models. In the current review, we discuss experimental HGSOC models in which resistance to platinum therapy and the use of novel therapeutics can be carefully studied. Panels of better-defined primary cell lines need to be established to capture the full spectrum of HGSOC subtypes. Further refinement of cell lines is obtained with a 3-dimensional culture model mimicking the tumor microenvironment. Alternatively, ex vivo ovarian tumor tissue slices are used. For in vivo studies, larger panels of ovarian cancer patient-derived xenografts (PDXs) are being established, encompassing all expression subtypes. Ovarian cancer PDXs grossly retain tumor heterogeneity and clinical response to platinum therapy is preserved. PDXs are currently used in drug screens and as avatars for patient response. The role of the immune system in tumor responses can be assessed using humanized PDXs and immunocompetent genetically engineered mouse models. Dynamic tracking of genetic alterations in PDXs as well as patients during treatment and after relapse is feasible by sequencing circulating cell-free tumor DNA and analyzing circulating tumor cells. We discuss how various models and methods can be combined to delineate the molecular mechanisms underlying platinum resistance and to select HGSOC patients other than BRCA1/2-mutation carriers that could potentially benefit from the synthetic lethality of PARP inhibitors. This integrated approach is a first step to improve therapy outcomes in specific subgroups of HGSOC patients.

Cisplatin-based chemotherapeutic regimens are the most frequently used (neo)adjuvant treatments for the majority of solid tumors. While platinum-based chemotherapeutic regimens have proven effective against highly proliferative malignant tumors, significant relapse and progression rates as well as decreased overall survival are still observed. Currently, it is known that sub-populations of chemoresistant cells share biological properties with cancer stem cells (CSC), which are believed to be responsible for tumor relapse, invasion and ultimately disease dissemination through acquisition of mesenchymal cell traits. In spite of concentrated efforts devoted to decipher the mechanisms underlying CSC chemoresistance and to design targeted therapeutics to these cells, proteomics has failed to unveil molecular signatures capable of distinguishing between malignant and non-malignant stem cells. This has hampered substantial developments in this complex field. Envisaging a novel rationale for an effective therapy, the current review summarizes the main cellular and molecular mechanisms underlying cisplatin resistance and the impact of chemotherapy challenge in CSC selection and clinical outcome. It further emphasizes the growing amount of data supporting a role for protein glycosylation in drug resistance. The dynamic and context-dependent nature of protein glycosylation is also comprehensively discussed, hence highlighting its potentially important role as a biomarker of CSC. As the paradigm of cancer therapeutics shifts towards precision medicine and patient-tailored therapeutics, we bring into focus the need to introduce glycomics and glycoproteomics in holistic pan-omics models, in order to integrate diverse, multimodal and clinically relevant information towards more effective cancer therapeutics.

Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance.

Although survival rates among patients with breast cancer have improved in recent years, those diagnosed with advanced disease with distant metastasis face a 5-year survival rate of less than 25%, making the management of these patients an area still in significant need of continued research. Selecting the optimal treatment order from among the variety of currently available therapy options presents a relevant challenge for medical oncologists. With the understanding that the majority of patients with breast cancer and those who succumb to this disease have HR-positive disease, this review will focus on treatment options and treatment order in patients with HR-positive advanced breast cancer. While endocrine therapy is considered the preferred treatment for first-line therapy in HR-positive/HER2-negative breast cancer, selection of the specific agent depends on the menopausal status of the patient. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is also recommended as first-line treatment in patients with ER-positive/HER2-negative disease. In patients with endocrine therapy-resistant disease, specific strategies include sequencing of other antiestrogen receptor agents, or agents that target other molecular pathways. Future treatment strategies for patients with primary or secondary resistance to endocrine therapy for advanced disease are discussed. These strategies include first-line therapy with high-dose fulvestrant or everolimus (in combination with exemestane or letrozole or with other endocrine therapies), use of the PI3K inhibitors (e.g., buparlisib, alpelisib, pictilisib, taselisib), entinostat, CDK 4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib), and novel selective estrogen receptor degradation agents that may enhance the targeting of acquired mutations in the ESR1 gene.

An increased tendency of genomic alterations during the life cycle of cells leads to genomic instability, which is a major driving force for tumorigenesis. A considerable fraction of tumor cells are tetraploid or aneuploid, which renders them intrinsically susceptible to mitotic aberrations, and hence, are particularly sensitive to the induction of mitotic catastrophe. Resistance to cell death is also closely linked to genomic instability, as it enables malignant cells to expand even in a stressful environment. Currently it is known that cells can die via multiple mechanisms. Mitotic catastrophe represents a step preceding apoptosis or necrosis, depending on the expression and/or proper function of several proteins. Mitotic catastrophe was proposed to be an onco-suppressive mechanism and the evasion of mitotic catastrophe constitutes one of the gateways to cancer development. Thus, stimulation of mitotic catastrophe appears to be a promising strategy in cancer treatment. Indeed, several chemotherapeutic drugs are currently used at concentrations that induce apoptosis irrespective of the cell cycle phase, yet are very efficient at triggering mitotic catastrophe at lower doses, significantly limiting side effects. In the present review we summarize current data concerning the role of mitotic catastrophe in cancer drug resistance and discuss novel strategies to break this link.

Since the discovery of 1α,25(OH)2D3 in the early 1970s, it has been widely accepted that this metabolite is responsible for the biological actions of vitamin D. Likewise, we have assumed that 25(OH)-19-nor-D3-dependent growth inhibition of human prostate PZ-HPV-7 cells was the result of its subsequent conversion to 1α,25(OH)2-19-nor-D3, catalyzed by CYP27B1 within the prostate cells. However, further in vitro studies in a reconstituted system using recombinant CYP27B1 revealed that 25(OH)-19-nor-D3 was hardly converted to 1α,25(OH)2-19-nor-D3 by the enzyme. The kinetic analysis of 1α-hydroxylation of 25(OH)D3 and 25(OH)-19-nor-D3 demonstrated that the k(cat)/K(m) for 25(OH)-19-nor-D3 is less than 0.1% of that for 25(OH)D3. When 25(OH)-19-nor-D3 was added to cultured PZ-HPV-7 cells, eight metabolites were detected, while no 1α,25(OH)2-19-nor-D3 was found. In addition, the time course of VDR translocation into the nucleus induced by 100 nM 25(OH)-19-nor-D3, and the subsequent transactivation of CYP24A1 gene were almost identical to those induced by 1 nM 1α,25(OH)2-19-nor-D3. These results strongly suggest that 25(OH)-19-nor-D3 binds directly to VDR as a ligand to transport VDR into the nucleus to induce CYP24A1 gene transactivation. Furthermore, knockdown of CYP27B1 gene did not affect the antiproliferative activity of 25(OH)-19-nor-D3, whereas VDR knockdown attenuated the effect, suggesting that the antiproliferative activity of 25(OH)-19-nor-D3 is VDR dependent but CYP27B1 independent. Finally, our recent studies using the same cell line demonstrate that 25(OH)D3 can act as a VDR agonist to induce gene transactivation. These findings suggest that vitamin D analogs without 1α-hydroxyl group could be developed as drugs for osteoporosis or cancer treatment.