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Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often the cell membrane. To better verify this hypothesis, we intentionally modify HB43, an ACP active against a wide variety of cancers. Sequence alignment of related ACPs by ADAPTABLE web server highlighted the conserved motifs that could be at the origin of the activity. In this study, we show that changing the order of amino acids in such motifs results in a significant loss of activity against colon and breast cancer cell lines. On the contrary, amino acid substitution in key motifs may reinforce or weaken the activity, even when the alteration does not perturb the amphipathicity of the helix formed by HB43 on liposomes mimicking their surface. NMR and MD simulations with different membrane models (micelles, bicelles, and vesicles) indicate that the activity reflects the insertion capability in cancer-mimicking serine-exposing membranes, supported by the insertion of N-terminal phenylalanine in the FAK motif and the anchoring to the carboxylate of phosphatidylserine by means of arginine side chains. [ABSTRACT FROM AUTHOR]

It is now admitted that in addition to acquired resistance, the tumor microenvironment contributes to the development of chemo-resistance and malignant progression. In a previous study, we showed that Dox induced apoptosis in FTC-133 cells by trigging JNK pathway. This process was accompanied by a decrease of thrombospondin-1 (TSP-1) expression. Moreover, exogenous TSP-1 or its C-terminal-derived peptide interact with receptor CD47 and are able to protect FTC-133 cells against Dox-induced apoptosis. Here, we investigated the involvement of TSP-1/CD47 interaction in a context of acquired multidrug resistance in FTC-133 cells. To that end, we established a Dox-resistant cell line (FTC-133R cells) which developed a resistance against Dox-induced apoptosis. Cell viability was evaluated by Uptiblue assay, nuclear Dox was measured by microspectrofluorimetry, caspase activity was measured by fluorescence of cleaved caspase-3 substrate, gene expression was evaluated by RT-PCR and protein expression was examined by western-blot. Our results showed that FTC-133R overexpressed the P-gp and were 15-fold resistant to Dox. JNK phosphorylation and Dox-induced apoptosis were reduced in FTC-133R cells. Expression of CD47 was increased in FTC-133R cells but TSP-1 expression presented similar levels in two cell lines. VPL restored Dox nuclear uptake and FTC-133R cell sensitivity to apoptosis and induced a decrease in CD47 mRNA expression. Moreover, knockdown of CD47 in FTC-133R cells induced an increase in JNK activation and sensitized FTC-133R cells to Dox. Our data suggest that CD47 is able to contribute to the protection of FTC-133R cells against Dox-induced apoptosis and/or to potentiate the acquired Dox resistance. [ABSTRACT FROM AUTHOR]

The Cardiovascular Continuum describes a sequence of events from cardiovascular risk factors to end‐stage heart disease. It includes conventional pathologies affecting cardiovascular functions such as hypertension, atherosclerosis or thrombosis and was traditionally considered from the metabolic point of view. This Cardiovascular Continuum, originally described by Dzau and Braunwald, was extended by O'Rourke to consider also the crucial role played by degradation of elastic fibers, occurring during aging, in the appearance of vascular stiffness, another deleterious risk factor of the continuum. However, the involvement of the elastin degradation products, named elastin‐derived peptides, to the Cardiovascular Continuum progression has not been considered before. Data from our laboratory and others clearly showed that these bioactive peptides are central regulators of this continuum, thereby amplifying appearance and evolution of cardiovascular risk factors such as diabetes or hypertension, of vascular alterations such as atherothrombosis and calcification, but also nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The Elastin Receptor Complex has been shown to be a crucial actor in these processes. We propose here the participation of these elastin‐derived peptides and of the Elastin Receptor Complex in these events, and introduce a revisited Cardiovascular Continuum based on their involvement, for which elastin‐based pharmacological strategies could have a strong impact in the future. [ABSTRACT FROM AUTHOR]

Telomerase is activated in human papillomavirus (HPV) positive cervical cancer and targeting telomeres offers a novel anticancer therapeutic strategy. In this study, the telomere targeting properties, the cytotoxic as well as the pro-apoptotic effects of hexane (IV-HE) and dichloromethane (IV-DF) fractions from Inula viscosa L. extracts were investigated on human cervical HeLa and SiHa cancer cells. Our data demonstrate that IV-HE and IV-DF extracts were able to inhibit cell growth in HeLa and SiHa cells in a dose-dependent manner and studied resistant cell lines exhibited a resistance factor less than 2 when treated with the extracts. IV-HE and IV-DF extracts were able to inhibit telomerase activity and to induce telomere shortening as shown by telomeric repeat amplification protocol and TTAGGG telomere length assay, respectively. The sensitivity of fibroblasts to the extracts was increased when telomerase was expressed. Finally, IV-HE and IV-DF were able to induce apoptosis as evidenced by an increase in annexin-V labeling and caspase-3 activity. This study provides the first evidence that the IV-HE and IV-DF extracts from Inula viscosa L. target telomeres induce apoptosis and overcome drug resistance in tumor cells. Future studies will focus on the identification of the molecules involved in the anticancer activity. [ABSTRACT FROM AUTHOR]

Degradation of elastin leads to the production of elastin-derived peptides (EDP), which exhibit several biological effects, such as cell proliferation or protease secretion. Binding of EDP on the elastin receptor complex (ERC) triggers lactosylceramide (LacCer) production and ERK1/2 activation following ERC Neu-1 subunit activation. The ability for ERC to transduce signals is lost during aging, but the mechanism involved is still unknown. In this study, we characterized an in vitro model of aging by subculturing human dermal fibroblasts. This model was used to understand the loss of EDP biological activities during aging. Our results show that ERC uncoupling does not rely on Neu-1 or PPCA mRNA or protein level changes. Furthermore, we observe that the membrane targeting of these subunits is not affected with aging. However, we evidence that Neu-1 activity and LacCer production are altered. Basal Neu-1 catalytic activity is strongly increased in aged cells. Consequently, EDP fail to promote Neu-1 catalytic activity and LacCer production in these cells. In conclusion, we propose, for the first time, an explanation for ERC uncoupling based on the age-related alterations of Neu-1 activity and LacCer production that may explain the loss of EDP-mediated effects occurring during aging. [ABSTRACT FROM AUTHOR]

Regulation of annexing concentration and localization were investigated in thyroid tissues of hypothyroid [methylthiouracil (MeSur) treatment], euthyroid (control) and hyperthyroid [thyroxine (T4) treatment] rats. A low level of circulating thyroid hormones induces a decrease of total thyroid calcium-binding protein concentration when compared with the concentration in unstimulated animals. Conversely, concentrations of annexing I, II and V increase. The accumulation of these proteins in two subcellular compartments (cytosolic and particulate fractions) can be reversed by addition of thyroid hormones. The finding of a specific increase in annexing concentration in thyroid-hormone-deficient rats, with a general decrease of the total calcium-binding protein content points to a very important role of these proteins in the cells Furthermore, hyperthyroidism gives opposite results. To investigate the transduction pathway of annexing I-, II- and V-induced biosynthesis by thyroid hormones in thyroid glands, we used cultured pig thyroid cells as in vitro model system. In previous work, we have shower that annexing concentrations and localization are under TSH control via the adenylate cyclase pathway. In the presence of MeSur (in the culture medium), the protein-binding iodine remains low, indicative of weak thyroid hormone synthesis (data not shown) and that the annexing content is unchanged. These results suggest that, in thyroid tissue, an indirect mechanism links thyroid hormones to annexing expressions via the TSH feed-back loop, and excludes autocrine regulation. [ABSTRACT FROM AUTHOR]

Background: Conventional chemotherapeutic treatment of colorectal cancer has low efficiency because of its high toxicity. Several studies identified natural compounds as potential antitumor agents by inducing cancer cell cycle arrest or apoptosis and exhibiting a potential synergy in drug combination therapy. Natural compounds derived from plants represent an important source of pharmacologic agents toward several diseases. For example, the Tunisian Thymelaeaceae plants are used in folk medicine for the treatment of different pathologies such as diabetes and hypertension., Objective: The Thymelaea hirsuta L. extracts were evaluated for their anti-tumoral activities and their adjuvant potential that could be used in conventional colorectal cancer therapy., Methods: Fractionation of total methanolic extract from the plant leaves provided 4 fractions using vacuum liquid chromatography. The cytotoxic activities of these fractions were tested toward colorectal cancer cells., Results: Ethyl acetate fraction (E2 fraction) induced cell cycle arrest and apoptosis by activating caspase-3. E2 fraction inhibited cell invasion by reducing integrin α5 expression and FAK phosphorylation. Moreover, E2 fraction potentialized colorectal cancer cells to 5-FU treatment., Conclusion: The selected plant Thymelaea hirsuta is the source of natural compounds that inhibited cell growth and invasion and induced cell cycle arrest in colorectal cancer cells. The most interesting result was their potential synergy in 5-FU combination treatment. Further analysis will identify the active compounds and confirm their role in chemotherapeutic treatment by sensitizing colorectal cancer cell to anti-cancer drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Tumor cells are confronted to a type I collagen rich environment which regulates cell proliferation and invasion. Biological aging has been associated with structural changes of type I collagen. Here, we address the effect of collagen aging on cell proliferation in a three-dimensional context (3D).We provide evidence for an inhibitory effect of adult collagen, but not of the old one, on proliferation of human fibrosarcoma HT-1080 cells. This effect involves both the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP-2. DDR2 and SHP-2 were less activated in old collagen. DDR2 inhibition decreased SHP-2 phosphorylation in adult collagen and increased cell proliferation to a level similar to that observed in old collagen.In the presence of old collagen, a high level of JAK2 and ERK1/2 phosphorylation was observed while expression of the cell cycle negative regulator p21CIP1 was decreased. Inhibition of DDR2 kinase function also led to an increase in ERK1/2 phosphorylation and a decrease in p21CIP1 expression. Similar signaling profile was observed when DDR2 was inhibited in adult collagen. Altogether, these data suggest that biological collagen aging could increase tumor cell proliferation by reducingthe activation of the key matrix sensor DDR2., Competing Interests: There is no conflict of interest.

The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered.

Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR).

Resistance to etoposide has been associated with the overexpression of P-glycoprotein and MRP1 in human tumor cells. However, the role of BCRP in resistance to etoposide has not been clearly established, especially the significance of arginine 482 mutations in drug transport (cellular uptake and efflux). Different levels of resistance to etoposide have been recently observed in cells expressing BCRP in terms of cytotoxicity. The aim of this work was to study the effects of these mutations on the functional involvement of BCRP in etoposide transport. HEK293 cells were transfected with an empty vector (HEK/V), the vector bearing the wild-type BCRP (HEK/R482), the mutant arginine-482-glycine (HEK/R482G) or the mutant arginine-482-threonine (HEK/R482T). MTT assay was used to study the cytotoxic effect of etoposide and [3H]-etoposide was used to determine cellular drug uptake and efflux. Data show that HEK/R482G cells displayed the highest levels of resistance to etoposide. Cellular [3H]-etoposide uptake was lower in HEK/R482, HEK/R482G and HEK/R482T cells compared to HEK/V cells. In addition, cellular [3H]-etoposide uptake in HEK/R482G was the lowest. Drug efflux measurements showed that fumitremorgin C was able to increase the residual cellular [3H]-etoposide uptake in BCRP-transfected cells and especially in HEK/R482G ones. Our data show that the R482G mutation in BCRP is able to increase efflux of etoposide and that mutation analysis at codon 482 may be of clinical importance in cancers treated with etoposide.

The selection pressure for resistance to chemotherapy is accompanied by the enhanced expression of ABC proteins and increased cellular glycosphingolipid content. Thus, a possible connection between glycosphingolipid metabolism and ABC proteins in drug resistance has been suggested. In the present study, we established two human multidrug-resistant (MDR) cell lines derived from MESSA sarcoma cells by culturing with increasing concentrations of doxorubicin (DX5 cells) or doxorubicin together with cyclosporin A (GARF cells). Both resistant cell lines overexpressed the MDR1 gene and the wild-type P-glycoprotein at the same level. The cyclosporin derivative PSC833, a potent inhibitor of P-glycoprotein, sensitized DX5 but not GARF cells to the cytotoxic effects of daunorubicin. Moreover, PSC833 increased the nuclear accumulation of daunorubicin and the cellular accumulation of [3H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [3H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [3H]-cyclosporin A. Sphingolipid analysis showed that the lactosylceramide level was 2.5- and 5-fold higher in DX5 and GARF cells, respectively, than in MESSA cells. Whereas the pharmacological inhibition of lactosylceramide synthesis was able to reverse only partially the resistance of GARF cells to daunorubicin without significant increase in nuclear accumulation of the drug, the same treatment before the co-treatment with PSC833 and daunorubicin increased the cytotoxic effect of daunorubicin and its nuclear accumulation. These data suggest a possible relationship between lactosylceramide levels and the resistance of P-glycoprotein to modulation by MDR modulators.