Efficacy Of Anticancer Therapy Research Articles

Abstract 1862: Natural compound E targets both lung cancer stem and non-cancer stem cells by disrupting HSP70 function

Abstract Solid malignant tumors are composed of heterogeneous populations of cancer cell, including cancer stem-like cells (CSCs), a specialized cell population characterized by the functional properties of self-renewal and have a potential to differentiate into various cancer subtypes. CSCs contribute to tumor recurrence, metastasis, and drug resistance, affecting efficacy of anticancer therapies. However, treatment strategies specifically targeting CSCs are limited, because current chemotherapeutic drugs mainly kill the bulk of sensitive cancer cells, leaving behind CSCs. These remaining CSCs are the main cause of cancer relapse and drug resistance. Hence, development of novel compounds eradicating CSCs are crucial for effective anticancer therapies. To identify novel CSC-targeting anticancer drugs, we have set-up a reporter system based on promoter activities of CSC markers that allows a standardized identification of CSCs. By using the reporter system, we screened a large natural products chemical library consisting 452 compounds with diverse chemical entity. And we selected 4 compounds. To further assess the inhibitory effect of these 4 compounds, we used sphere-forming assay with NSCLC cell lines. Through these processes, we finally chose Compound E. We found that treatment with Compound E significantly reduced the subpopulation of NSCLC CSC. We confirmed the inhibitory effects of Compound E on NSCLC CSCs by performing sphere formation analysis and flow cytometry-based ALDH detection assay. Treatment with Compound E also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis. In line with these in vitro results, orally administered Compound E significantly suppressed the growth of xenograft tumors derived from both NSCLC cell lines and patient-derived tumor tissues. To determine the tumor forming capacity of tumor cells derived from the vehicle or Compound E-treated mice, we carried out a limiting dilution tumor-propagating assay. NOD/SCID mice were transplanted with tumor cells over a range from doses unable to initiate tumor growth to dose that initiated tumor formation. Tumor cells derived from Compound E-treated mice displayed reduced tumor forming capacity compared to vehicle treated mice. Mechanistically, Compound E disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data collectively unveil the potential of Compound E as a natural Hsp70 inhibitor targeting both CSC and non-CSC populations of NSCLC. Citation Format: Seung Yeob Hyun, Huong Thuy Le, HongLan Pei, Simin Chun, Hye-Young Min, Suckchang Hong, Ho-Young Lee. Natural compound E targets both lung cancer stem and non-cancer stem cells by disrupting HSP70 function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1862.

Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics.

The search for effective strategies to inhibit tumorigenesis remains one of the most relevant scientific challenges. Among the most promising approaches is the direct modulation of the function of short non-coding RNAs, particularly miRNAs. These molecules are propitious targets for anticancer therapy, since they perform key regulatory roles in a variety of signaling cascades related to cell proliferation, apoptosis, migration, and invasion. The development of pathological states is often associated with deregulation of miRNA expression. The present review describes in detail the strategies aimed at modulating miRNA activity that invoke antisense oligonucleotide construction, such as small RNA zippers, miRNases (miRNA-targeted artificial ribonucleases), miRNA sponges, miRNA masks, anti-miRNA oligonucleotides, and synthetic miRNA mimics. The broad impact of developed miRNA-based therapeutics on the various events of tumorigenesis is also discussed. Above all, the focus of this review is to evaluate the results of the combined application of different miRNA-based agents and chemotherapeutic drugs for the inhibition of tumor development. Many studies indicate a considerable increase in the efficacy of anticancer therapy as a result of additive or synergistic effects of simultaneously applied therapies. Different drug combinations, such as a cocktail of antisense oligonucleotides or multipotent miRNA sponges directed at several oncogenic microRNAs belonging to the same/different miRNA families, a mixture of anti-miRNA oligonucleotides and cytostatic drugs, and a combination of synthetic miRNA mimics, have a more complex and profound effect on the various events of tumorigenesis as compared with treatment with a single miRNA-based agent or chemotherapeutic drug. These data provide strong evidence that the simultaneous application of several distinct strategies aimed at suppressing different cellular processes linked to tumorigenesis is a promising approach for cancer therapy.

Role of the Microbiota in Primary Lung Cancer Initiation and Progression

Abstract Lung cancer is the leading cause of cancer-related death in men in 87 countries and in women in 26 countries. The commensal microbiota lives on the epithelial barriers of the host and is vital for the health of the organism. Specific microbial species have been described to affect neoplastic pathology both at the gastrointestinal tract level and systematically in organs that are not normally associated with the gut microbiota. Studies have revealed the importance of the gut microbiota in the efficacy of anti-cancer therapies (chemo and immunotherapy) However, the role of lung microbiome in lung cancer remains largely unknown. We aimed to study the role of the lung microbiota during lung carcinogenesis progression in the context of p53/K-ras mutation and its impact on the tumor microenvironment. To further analyze the impact of the lung microbiota on lung cancer initiation, P53-Kras mutant germ-free mice will be colonized by intranasal instillation with bacteria identified in human lungs samples from lung cancer patients such as Variovorax paradoxus (V.paradoxus) and Acidovorax temperans (A.temperans) and the tumor burden will be calculated. Our data indicates Germ-free mice instilled with V. paradoxus trended towards an increase tumor burden compared to respective controls while A. temperans -associated germ-free mice seems to delay tumor growth. Germ-free mice, at 18 and 24 weeks post-Ad-Cre virus instillation, tends to have an increased tumor burden than their SPF counterparts. Also, changes in immune infiltrate were observed after flow cytometric analysis with preliminary data showing a decrease in CD45 positives cells the cells in mice instilled with V. paradoxus as well as an increase in Monocytes and Macrophages populations.

Targeting Tumor Microenvironment for Cancer Therapy.

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.

Cellular senescence: a promising strategy for cancer therapy

Cellular senescence, a permanent state of cell cycle arrest, is believed to have originally evolved to limit the proliferation of old or damaged cells. However, it has been recently shown that cellular senescence is a physiological and pathological program contributing to embryogenesis, immune response, and wound repair, as well as aging and age-related diseases. Unlike replicative senescence associated with telomere attrition, premature senescence rapidly occurs in response to various intrinsic and extrinsic insults. Thus, cellular senescence has also been considered suppressive mechanism of tumorigenesis. Current studies have revealed that therapy-induced senescence (TIS), a type of senescence caused by traditional cancer therapy, could play a critical role in cancer treatment. In this review, we outline the key features and the molecular pathways of cellular senescence. Better understanding of cellular senescence will provide insights into the development of powerful strategies to control cellular senescence for therapeutic benefit. Lastly, we discuss existing strategies for the induction of cancer cell senescence to improve efficacy of anticancer therapy.

Normalization of Tumor Vasculature by Oxygen Microbubbles with Ultrasound.

Tumor microenvironment influences the efficacy of anti-cancer therapies. The dysfunctional tumor vasculature limits the efficiency of oxygenation and drug delivery to reduce treatment outcome. A concept of tumor vascular normalization (VN), which inhibits angiogenesis to improve vessel maturity, blood perfusion, and oxygenation, has been demonstrated under the anti-angiogenic therapy. The efficiency of drug delivery and penetration is increased by enhancing perfusion and reducing interstitial fluid pressure during the time window of VN. However, anti-angiogenic agents only induce transient VN and then prune vessels to aggravate tumor hypoxia. To repair tumor vessels without altering vessel density, we proposed to induce tumor VN by local oxygen release via oxygen microbubbles with ultrasound. With tumor perfusion enhancement under ultrasound contrast imaging tracing, the time window of VN was defined as 2-8 days after a single oxygen microbubble treatment. The enhanced tumor oxygenation after oxygen microbubble treatment inhibited hypoxia inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway to improve the morphology and function of tumor vasculature. The pericyte coverage and Hoechst penetration of tumor vessels increased without any changes to the vessel density. Finally, the intratumoral accumulation of anti-cancer drug doxorubicin could be increased 3-4 folds during tumor VN. These findings demonstrate that regulating tumor oxygenation by oxygen microbubbles could normalize dysfunctional vessels to enhance vascular maturity, blood perfusion, and drug penetration. Furthermore, ultrasound perfusion imaging provides a simple and non-invasive way to detect the VN time window, which increases the feasibility of VN in clinical cancer applications.

Drug-adapted cancer cell lines as preclinical models of acquired resistance.

Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

The NCI Transcriptional Pharmacodynamics Workbench: A Tool to Examine Dynamic Expression Profiling of Therapeutic Response in the NCI-60 Cell Line Panel.

: The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs. SIGNIFICANCE: The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.

Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance

A mammalian cell houses two genomes located separately in the nucleus and mitochondria. During evolution, communications and adaptations between these two genomes occur extensively to achieve and sustain homeostasis for cellular functions and regeneration. Mitochondria provide the major cellular energy and contribute to gene regulation in the nucleus, whereas more than 98% of mitochondrial proteins are encoded by the nuclear genome. Such two-way signaling traffic presents an orchestrated dynamic between energy metabolism and consumption in cells. Recent reports have elucidated the way how mitochondrial bioenergetics synchronizes with the energy consumption for cell cycle progression mediated by cyclin B1/CDK1 as the communicator. This review is to recapitulate cyclin B1/CDK1 mediated mitochondrial activities in cell cycle progression and stress response as well as its potential link to reprogram energy metabolism in tumor adaptive resistance. Cyclin B1/CDK1-mediated mitochondrial bioenergetics is applied as an example to show how mitochondria could timely sense the cellular fuel demand and then coordinate ATP output. Such nucleus-mitochondria oscillation may play key roles in the flexible bioenergetics required for tumor cell survival and compromising the efficacy of anti-cancer therapy. Further deciphering the cyclin B1/CDK1-controlled mitochondrial metabolism may invent effect targets to treat resistant cancers.

Tissue necrosis and its role in cancer progression.

Great efforts have been made in revealing the mechanisms governing cancer resistance and recurrence. The in-situ effects of cell death, caused by hypoxia and metabolic stress, were largely studied in association with inflammation. However, in this work, we focused on the direct effects of necrosis on cancer promotion and on the tumor microenvironment. The conditions leading to cell necrosis, upon nutrient and oxygen deprivation, were recapitulated in-vitro and were used to generate samples for computational proteomic analysis. Under these conditions, we identified clusters of enriched pathways that may be involved in tumor resistance, leading to cancer recurrence. We show that the content of necrotic cells enhances angiogenesis and proliferation of endothelial cells, induces vasculature, as well as increases migration, invasion, and cell-cell interactions. In-vivo studies, where MDA-MB-231 xenografts were exposed to necrotic lysates, resulted in an increase in both proliferation and angiogenesis. Histological analysis of tumor tissues revealed high expression levels of key mediators that were identified by proteomic analysis. Moreover, when cells were injected systemically, coupled with necrotic lysates, a higher number of large lesions was detected in the lung. Finally, using xenografts, we demonstrated that combining an antagonist of a necrotic signal with an anticancer treatment potentiates the prolonged therapeutic effect. This approach suggests a paradigm shift in which targeting late necrotic-secreted factors may increase survival and enhance the efficacy of anticancer therapy.

Blockade of Hypoxia: The Impact on Tumor Growth in an Experimental Tumor Model

Background: Tumor microenvironment is an active factor participating in immunoregulation, thereby preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia as a major characteristic of solid tumors causes the expression of Hypoxia-Inducible Factor-1α (HIF-1α). This is a transcription factor that mediates hypoxic responses of tumor cells and involves in the expression of tumor immunosuppression-related genes. Materials and Methods: In this study, we used a mouse 4T1 breast cancer model.Results: Our obtained data revealed that in vivo administration of PX-478, an inhibitor of oxygen sensitive HIF-1α, reduced the expression of Forkhead box P3 (Foxp3) transcript, a molecule that is directly controlled by HIF-1. The level of vascular endothelial growth factor, another gene controlled by HIF-1, remained unchanged. The observed results were in correlation with delayed tumor growth in tumor-bearing mice.Conclusion: Our findings indicate that the reduction in Foxp3 expression through HIF-1α inhibition using PX-478 may contribute to tumor regression.

Morphological changes in the ovarian carcinoma cells of Wistar rats induced by chemotherapy with cisplatin and dioxadet.

The development of new express methods for the analysis of the efficacy of anti-cancer therapy on the cellular level is highly desirable for the analysis of chemotherapeutic agent performance. In this paper we suggest the use of parameters of cell morphology determined by holographic microscopy and tomography for the effective label free quantitative analysis of cell viability under antitumor chemotherapy and thus of cytostatic agent efficacy. As shown, measured phase shifts and cell morphology change dramatically as a result of chemotherapy and depend strongly on the cell type and agent applied. Experimentally, a comparative analysis of the antitumor efficacy of the two cytostatics, cisplatin and dioxadet, that are commonly used for chemotherapy of disseminated ovarian carcinoma has been performed. The experiments were carried out on the Wistar rat model. An essential difference in the morphology of cells, both normal (erythrocytes) and cancerous, present in ascitic fluid taken from the non-treated group of rats and the groups treated with either dioxadet or cisplatin, has been observed. The results obtained can be interpreted as an indication of the antitumor performance of both cytostatics at the cellular level and as a demonstration of the higher efficacy of therapy with dioxadet as compared to that with cisplatin. Differences in cell morphology are suggested to be applied as quantitative markers of cell viability and cytostatic agent efficacy. The conclusions made are supported by a comparison with the results of recent experiments based on survival rates of laboratory animals treated with these agents..

Transfusion Therapy: Is There a Link with Cancer Recurrence?

To present an updated narrative review of the available clinical evidence regarding the impact of perioperative anemia and blood product administration on cancer recurrence and mortality. To address some of the current strategies to reduce blood transfusions and their safety in oncologic surgery. Both anemia and packed red blood cells (pRBCs) transfusions have been associated with an increased risk of recurrence and mortality in certain solid malignancies. Anemia directly stimulates protective mechanisms against apoptosis of cancer cells while promoting a favorable micro-environment and reducing the efficacy of anticancer therapies. When transfusion occurs, transfusion-related immunomodulation (TRIM) mediates the immunosuppression and inflammation responsible for the impairment of the host immune system to appropriately eliminate cancer cells. However, pRBCs can also promote tumor growth by non-TRIM mechanisms. Evidence of the negative impact of perioperative anemia and blood transfusions on cancer recurrence and mortality should raise concern about the appropriate timing of blood transfusions in patients with cancer undergoing surgical procedures. Blood sparing strategies such as acute normovolemic hemodilution, autologous pRBCs transfusions and intraoperative cell savage appear to be safe means to minimize allogeneic pRBCs in the context of cancer surgery, although the safety of these strategies has not been rigorously tested in randomized controlled trials.

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study.

Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population. INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017. Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p=0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p<0.0001. Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.

Phosphoglycerate dehydrogenase inhibition induces p-mTOR-independent autophagy and promotes multilineage differentiation in embryonal carcinoma stem-like cells

Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor-initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker β3-tubulin. Furthermore, PHGDH inhibition promotes p-mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co-expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs.

Ultra-small Albumin Templated Gd/Ru Composite Nanodots for In Vivo Dual modal MR/Thermal Imaging Guided Photothermal Therapy.

Multifunctional theranostic nanoagents which realize precise diagnosis and treatment of tumors are attracting increasing interests in recent years. However, efficient and controlled synthesis of ultra-small noble metal nanoagents remains a challenge. Here, monodisperse Gd/Ru@BSA nanodots (GRBNDs) are successfully fabricated via a totally "green", "one-pot" protocol for in situ reduction of Ru(III) and biomineralization of Gd(III) in the presence of albumin. The as-prepared nanoagent possesses the features of being ultra small in size (≈6.7 nm), having strong colloidal stability, and thermal stability as well as high photothermal conversion efficiency (η = 50.7%). As expected, the GRBNDs achieve a significant efficacy of anticancer therapy under LASER activation both in vitro and in vivo. It also exhibits superior T1 -weighted magnetic resonance (MR) imaging ability due to its high longitudinal relaxivity value (r1 = 10.98 × 10-3 m-1 s-1 ). Moreover, it is demonstrated to be renal clearable with negligible systemic toxicity. This work highlights a straightforward and repeatable approach for synthesizing highly effective and multifunctional noble metal nanoagent of great clinical promising for cancer theranostics.

Assessment of DNA-PKcs kinase activity by quantum dot\u2013based microarray

Therapeutic efficacy against cancer is often based on a variety of DNA lesions, including DNA double-strand breaks (DSBs) which are repaired by homologous recombination and non-homologous end joining (NHEJ) pathways. In the past decade, the functions of the DNA repair proteins have been described as a potential mechanism of resistance in tumor cells. Therefore, the DNA repair proteins have become targets to improve the efficacy of anticancer therapy. Given the central role of DNA-PKcs in NHEJ, the therapeutic efficacy of targeting DNA-PKcs is frequently described as a strategy to prevent repair of treatment-induced DNA damage in cancer cells. The screening of a new inhibitor acting as a sensitizer requires the development of a high-throughput tool in order to identify and assess the most effective molecule. Here, we describe the elaboration of an antibody microarray dedicated to the NHEJ pathway that we used to evaluate the DNA-PKcs kinase activity in response to DNA damage. By combining a protein microarray with Quantum-Dot detection, we show that it is possible to follow the modification of phosphoproteomic cellular profiles induced by inhibitors during the response to DNA damage. Finally, we discuss the promising tool for screening kinase inhibitors and targeting DSB repair to improve cancer treatment.

PDGF-AB rich-trombocyte lysate supplementation from breast cancer patients increased the proliferation of breast cancer stem cells

Background: Thrombocytosis in breast cancer (BC) patient was thought to play a role in the invasiveness of breast cancer stem cells (BCSCs). Modification of tumor microenvironment was proposed to increase the efficacy of anticancer therapy. This study was aimed to analyze the effect of platelet lysate (PL) as well as its PDGF-AB content as a tumor microenvironment on (CD24-/CD44+) BCSC proliferation.Methods: This was an experimental study that treated culture of BCSCs with PL from breast cancer (BC) patients or healthy donors. Venous blood from all subjects were subjected to prior hematology test and then processed to obtain platelet rich plasma (PRP). Platelet counts in PRP were determined. PRP was processed to obtain PL. PDGF-AB contents in PL were measured. PL at concentrations of 0.01% (v/v) was supplemented into DMEM-F12 medium and used for culturing BCSCs (CD24-/CD44+ cells). After 48 hours, total cell count, population doubling time (PDT), and cell viability were calculated and their correlation with platelet count and PDGF-AB levels were analyzed.Results: BC patients (n=5) had higher platelet counts and PDGF-AB levels in PL compared to healthy donors (n=15), (p=0.02). PL from BC patients could stimulate the proliferation of BCSCs higher than healthy donors (p&lt;0.001) and showed lower PDT value (p=0.001). Cell proliferation and PDT showed strong correlation with PDGF-AB level. This observation suggests that PDGF-AB has a role on BCSCs proliferation. PL showed no effect on BCSCs viability.Conclusion: Breast cancer patient platelet lysate stimulated BCSC proliferation.