Showing papers on "Doxorubicin published in 2018"
TL;DR: The idea of this review is to bring up to date the recent findings of the mechanism of doxorubicin cardiomyopathies such as calcium dysregulation, endoplasmic reticulum stress, impairment of progenitor cells, activation of immune, ubiquitous system and some other parameters.
349 citations
TL;DR: This work provides a new, generalizable framework for using nanoparticle-based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade.
Abstract: Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models. Delivery of DOX via nanodiscs triggered immunogenic cell death of cancer cells and exerted antitumor efficacy without any overt off-target side effects. "Priming" tumors with DOX-carrying nanodiscs elicited robust antitumor CD8+ T cell responses while broadening their epitope recognition to tumor-associated antigens, neoantigens, and intact whole tumor cells. Combination chemoimmunotherapy with nanodiscs plus anti-programmed death 1 therapy induced complete regression of established CT26 and MC38 colon carcinoma tumors in 80 to 88% of animals and protected survivors against tumor recurrence. Our work provides a new, generalizable framework for using nanoparticle-based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade.
237 citations
TL;DR: Investigation into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role and correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorbicin.
Abstract: Cancer cell resistance to therapeutics can result from acquired or de novo-mediated factors. Here, we have utilised advanced breast cancer cell culture models to elucidate de novo doxorubicin resistance mechanisms. The response of breast cancer cell lines (MCF-7 and MDA-MB-231) to doxorubicin was examined in an in vitro three-dimensional (3D) cell culture model. Cells were cultured with Matrigel™ enabling cellular arrangements into a 3D architecture in conjunction with cell-to-extracellular matrix (ECM) contact. Breast cancer cells cultured in a 3D ECM-based model demonstrated altered sensitivity to doxorubicin, when compared to those grown in corresponding two-dimensional (2D) monolayer culture conditions. Investigations into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role. This finding correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorubicin. Inhibition of integrin signalling in combination with doxorubicin significantly reduced breast cancer cell viability. Furthermore, breast cancer cells grown in a 3D ECM-based model demonstrated a significantly reduced proliferation rate in comparison to cells cultured in 2D conditions. Collectively, these novel findings reveal resistance mechanisms which may contribute to reduced doxorubicin sensitivity.
224 citations
TL;DR: A strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which is term medium-dose intermittent chemotherapy (MEDIC), where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, thereby maximizing anti-cancer activity.
213 citations
TL;DR: It is shown that when TNBC cells are treated with chemotherapy, the surviving cells turn on genes that enable them to escape killing by the immune system, and hypoxia-inducible factors (HIFs), which are known to promote metastasis of TNBC, are identified as responsible for this countertherapeutic effect.
Abstract: Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47+CD73+PDL1+ breast cancer cells. Genetic or pharmacological inhibition of hypoxia-inducible factors (HIFs) blocked chemotherapy-induced enrichment of CD47+CD73+PDL1+ TNBC cells, which were also enriched in the absence of chemotherapy by incubation under hypoxic conditions, leading to T cell anergy or death. Treatment of mice with cytotoxic chemotherapy markedly increased the intratumoral ratio of regulatory/effector T cells, an effect that was abrogated by HIF inhibition. Our results delineate an HIF-dependent transcriptional mechanism contributing to TNBC progression and suggest that combining chemotherapy with an HIF inhibitor may prevent countertherapeutic induction of proteins that mediate evasion of innate and adaptive antitumor immunity.
212 citations
TL;DR: An innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.
Abstract: Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naive T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.
194 citations
TL;DR: In this article, the authors explored the mechanisms and new drug targets to treat DOX-induced cardiotoxicity in rats and mice, and showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, and caused histopathological and ECG changes in rat and mice.
Abstract: Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity.
182 citations
TL;DR: Based on the synergistic apoptosis‐inducing effects of DOX and CDDP, CDDPHANG/DOX reveals an evidently enhanced antitumor efficacy compared to free drugs and their combination, indicating its great prospects for the chemotherapy of osteosarcoma.
Abstract: Osteosarcoma is one of the most serious bone malignancies with rapid speed of deterioration and low survival rate in children and teenagers. Chemotherapy is an important treatment for osteosarcoma, while the conventional small-molecule therapeutics exhibit low efficacies and severe side effects in the clinic. Drug-delivery platforms based on nanotechnology, particularly for self-stabilized delivery platforms with prolonged blood circulation, enhanced intratumoral accumulation, improved antitumor efficacy, and diminished side effects, may break the deadlock on osteosarcoma chemotherapy. Here, a cisplatin (CDDP)-crosslinked hyaluronic acid (HA) nanogel (CDDPHANG) is prepared for effective delivery of doxorubicin (DOX) to treat osteosarcoma. Importantly, both DOX and CDDP have led clinically used antitumor drugs, and CDDP acts as a crosslinker and ancillary anticarcinogen to prevent the premature release of DOX and to achieve synergistic therapeutic performance. Because of the enhanced stability of the nanogel, this CDDP-crosslinked DOX-loaded nanomedicine (CDDPHANG/DOX) exhibits an obviously prolonged circulation time compared to free drugs. Moreover, after valid tumor accumulation, DOX and CDDP are synergistically delivered into the tumor cells and synchronously released into the intracellular acidic environment. Based on the synergistic apoptosis-inducing effects of DOX and CDDP, CDDPHANG/DOX reveals an evidently enhanced antitumor efficacy compared to free drugs and their combination, indicating its great prospects for the chemotherapy of osteosarcoma.
159 citations
TL;DR: The development of drug delivery systems for doxorubicin are considered, which improve the therapeutic window (efficacy and safety) and which address limitations of the current FDA-approved doxorbicin formulations.
Abstract: Doxorubicin is a widely used chemotherapy agent. Despite its utility, several adverse side effects, especially its irreversible cardiotoxicity and reversible nephrotoxicity, have prompted the development of liposomal carriers, many of which are FDA approved. Antitumor efficacies of approved liposome-Dox preparations can equal or exceed that of conventional doxorubicin. Because these liposomes carriers accumulate in solid tumor tissues via an enhanced permeation and retention (EPR) effect, these carriers have an improved safety profile. Nevertheless, a significant problem with the current drug delivery preparations of doxorubicin is a lack of efficacy toward tumors that exhibit multidrug resistance. In this review, we consider the development of drug delivery systems for doxorubicin, which improve the therapeutic window (efficacy and safety) and which address limitations of the current FDA-approved doxorubicin formulations.
153 citations
TL;DR: N nanoscaled RBCs (RAs) containing oxyHb and gas-generating agent ammonium bicarbonate are prepared for co-loading and controlled release of ICG and DOX to achieve synergistic effects of PTT/PDT and chemotherapy against breast cancer.
147 citations
TL;DR: By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer.
TL;DR: It is shown that chemotherapy agents can induce HSP90AA1 expression in osteosarcoma cells and HSP 90AA1, acting as an important regulator of autophagy, is a critical factor in the development of osteosARcoma chemoresistance both in vitro and in vivo.
Abstract: Osteosarcoma is the most common primary bone tumor in children and adolescents Unfortunately, osteosarcoma treatments often fail due to the development of chemoresistance, of which the underlying molecular mechanisms still remain unclear In this study, we demonstrated that HSP90AA1 gene is responsible for drug resistance in osteosarcoma through an autophagy-related mechanism shRNAs were transfected into osteosarcoma cells for knockdown of HSP90AA1 gene Stable HSP90AA1 overexpressing osteosarcoma cell lines were obtained by lentivirus infection mRNA and protein expressions of HSP90AA1 in osteosarcoma cells were tested by quantitative real-time PCR and western blot, respectively Autophagy of osteosarcoma cells was detected by western blot of LC3, transmission electron microscopy and fluorescence microscope mRFP-GFP-LC3 lentiviral transfection was also performed to detect autophagic flux NOD/SCID mices were inoculated with MG-63 tumor cells transfected with HSP90AA1 specific shRNA TUNEL and LC3 staining were performed to detect apoptosis and autophagy of resected tumor tissues Doxorubicin, cisplatin, and methotrexate, which are commonly used in chemotherapy, each induced HSP90AA1 upregulation in human osteosarcoma cells Suppression of HSP90AA1 restored the sensitivity of osteosarcoma cells to chemotherapy both in vivo and in vitro Mechanism study indicated that autophagy is responsible for the chemoresistance in osteosarcoma cells HSP90AA1 increased drug resistance by inducing autophagy and inhibiting apoptosis Suppression of HSP90AA1 diminished autophagic protection in response to chemotherapy in osteosarcoma cells Moreover, HSP90AA1 promotes autophagy through PI3K/Akt/mTOR pathway and inhibits apoptosis through JNK/P38 pathway We showed that chemotherapy agents can induce HSP90AA1 expression in osteosarcoma cells And HSP90AA1, acting as an important regulator of autophagy, is a critical factor in the development of osteosarcoma chemoresistance both in vitro and in vivo HSP90AA1 provides a novel therapeutic target for improving osteosarcoma treatment
TL;DR: A facile strategy is reported to construct a versatile DNA nanostructure as a co-delivery vector of RNA interference and chemodrugs to combat multidrug-resistant tumor (MCF-7R) in vitro and in-vivo.
Abstract: Multidrug resistance (MDR) is a major obstacle in the clinical treatment of cancer. Herein, a facile strategy is reported to construct a versatile DNA nanostructure as a co-delivery vector of RNA interference (RNAi) and chemodrugs to combat multidrug-resistant tumor (MCF-7R) in vitro and in vivo. In the tailored nanocarrier, two linear small hairpin RNA (shRNA) transcription templates targeting MDR-associated genes (gene of P-glycoprotein, a typical drug efflux pump; and gene of survivin, a representative anti-apoptotic protein) are precisely organized in the chemodrug (doxorubicin, DOX) pre-loaded DNA origami. With the incorporation of active targeting and controlled-release elements, these multifunctional DNA nanocarriers can successfully enter the target MCF-7R cells and synergistically inhibit tumor growth without apparent systemic toxicity. This tailored DNA nanoplatform, which combines RNAi therapy and chemotherapy, provides a new strategy for the treatment of multidrug-resistant tumors.
TL;DR: The liberated NPs from the dead or dying cells continue to respond to the ubiquitous aqueous environment to sufficiently release DOX once unpacked, leading to severe cytotoxicity to neighboring cells (neighboring effect), and the continuously released free DOX molecules can readily diffused through the tumor extracellular matrix to enhance drug penetration to deep tumor tissue.
Abstract: Insufficient drug release as well as poor drug penetration are major obstacles for effective nanoparticles (NPs)-based cancer therapy. Herein, the high aqueous instability of amorphous calcium carbonate (ACC) is employed to construct doxorubicin (DOX) preloaded and monostearin (MS) coated "Pandora's box" (MS/ACC-DOX) NPs for lipase-triggered water-responsive drug release in lipase-overexpressed tumor tissue to induce a neighboring effect and enhance drug penetration. MS as a solid lipid can prevent potential drug leakage of ACC-DOX NPs during the circulatory process, while it can be readily be disintegrated in lipase-overexpressed SKOV3 cells to expose the ACC-DOX core. The high aqueous instability of ACC will lead to burst release of the encapsulated DOX to induce apoptosis and cytotoxicity to kill the tumor cells. The liberated NPs from the dead or dying cells continue to respond to the ubiquitous aqueous environment to sufficiently release DOX once unpacked, like the "Pandora's box", leading to severe cytotoxicity to neighboring cells (neighboring effect). Moreover, the continuously released free DOX molecules can readily diffused through the tumor extracellular matrix to enhance drug penetration to deep tumor tissue. Both effects contribute to achieve elevated antitumor benefits.
TL;DR: PI3K&ggr; blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity.
Abstract: Background: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardio...
TL;DR: The dual inhibition of the PD-1/PD-L1 axis elicits significant immune response and presents a robust effect in lengthening tumor recurrent time and inhibiting tumor metastasis, Consequently, the multifunctional nanoplatform provides a potential strategy of synergetic chemotherapy and immunotherapy.
Abstract: Hypoxia is reported to participate in tumor progression, promote drug resistance, and immune escape within tumor microenvironment, and thus impair therapeutic effects including the chemotherapy and advanced immunotherapy. Here, a multifunctional biomimetic core-shell nanoplatform is reported for improving synergetic chemotherapy and immunotherapy. Based on the properties including good biodegradability and functionalities, the pH-sensitive zeolitic imidazolate framework 8 embedded with catalase and doxorubicin constructs the core and serves as an oxygen generator and drug reservoir. Murine melanoma cell membrane coating on the core provides tumor targeting ability and elicits an immune response due to abundance of antigens. It is demonstrated that this biomimetic core-shell nanoplatform with oxygen generation can be partial to accumulate in tumor and downregulate the expression of hypoxia-inducible factor 1α, which can further enhance the therapeutic effects of chemotherapy and reduce the expression of programmed death ligand 1 (PD-L1). Combined with immune checkpoints blockade therapy by programmed death 1 (PD-1) antibody, the dual inhibition of the PD-1/PD-L1 axis elicits significant immune response and presents a robust effect in lengthening tumor recurrent time and inhibiting tumor metastasis. Consequently, the multifunctional nanoplatform provides a potential strategy of synergetic chemotherapy and immunotherapy.
TL;DR: Cardiac specific-overexpression of CTRP3 preserved heart dysfunction, and attenuated cardiac inflammation and cell loss induced by DOX in vivo and in vitro, showing therapeutic potential for the treatment of DOX cardiotoxicity.
TL;DR: It is demonstrated, for the first time, that a SO2 polymer prodrug, acting as a stimuli-responsive nanocarrier to codeliver DOX, can efficiently inhibit the proliferation of MDR tumor cells, which may offer a new weapon for combating MDR in cancer therapy.
TL;DR: Dox@PVP-AuNPs can be considered as an potential drug delivery system for effective treatment of human lung cancer and highly upregulates the expression of tumor suppressor genes and induces intrinsic apoptosis in lung cancer cells.
Abstract: Development of drug delivery system conjugated with doxorubicin (dox) on the surface of AuNPs with polyvinylpyrrolidone (Dox@PVP-AuNPs), we have demonstrated that human lung cancer cells can significantly overcome by the combination of highly effective cellular entry and responsive intracellular release of doxorubicin from Dox@PVP-AuNPs complex. Previously drug release from doxorubicin-conjugated AuNPs was confirmed by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between doxorubicinyl groups and AuNPs. Dox@PVP-AuNPs achieved enhanced inhibition of lung cancer cells growth than free Doxorubicin and PVP-AuNPs. The in vitro cytotoxic effect of PVP-AuNPs, free Dox and Dox@PVP-AuNPs inhibited the proliferation of human lung cancer cells with IC50 concentration. Compared with control cells, PVP-AuNPs and free Dox, Dox@PVP-AuNPs can increases ROS generation, sensitize mitochondrial membrane potential and induces both early and late apoptosis in lung cancer cells. Moreover, Dox@PVP-AuNPs highly upregulates the expression of tumor suppressor genes than free Dox and PVP-AuNPs and induces intrinsic apoptosis in lung cancer cells. From the results, Dox@PVP-AuNPs can be considered as an potential drug delivery system for effective treatment of human lung cancer.
TL;DR: Development of multi drug resistance in OXA‐R cells was confirmed by exposing the resistance cells to oxaliplatin, 5‐FU, and doxorubicin, and in vivo studies in nude mice also confirms the same.
Abstract: Oxaliplatin (OXA), is a third generation platinum drug used as first-line chemotherapy in colorectal cancer (CRC). Cancer cells acquires resistance to anti-cancer drug and develops resistance. ATP-binding cassette (ABC) drug transporter ABCG2, one of multidrug resistance (MDR) protein which can effectively discharge a wide spectrum of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular concentration of these drugs. Role of ABCG2 and plausible molecular signaling pathways involved in Oxaliplatin-Resistant (OXA-R) colon cancer cells was evaluated in the present study. OXA resistant LoVo cells was developed by exposing the colon cells to OXA in a dose-dependent manner. Development of multi drug resistance in OXA-R cells was confirmed by exposing the resistance cells to oxaliplatin, 5-FU, and doxorubicin. OXA treatment resulted in G2 phase arrest in parental LoVo cells, which was overcome by OXA-R LoVo cells. mRNA and protein expression of ABCG2 and phosphorylation of NF-κB was significantly higher in OXA-R than parental cells. Levels of ER stress markers were downregulated in OXA-R than parental cells. OXA-R LoVo cells exposed to NF-κB inhibitor QNZ effectively reduced the ABCG2 and p-NF-κB expression and increased ER stress marker expression. On other hand, invasion and migratory effect of OXA-R cells were found to be decreased, when compared to parental cells. Metastasis marker proteins also downregulated in OXA-R cells. ABCG2 inhibitor verapamil, downregulate ABCG2, induce ER stress markers and induces apoptosis. In vivo studies in nude mice also confirms the same.
TL;DR: A genome-wide integrative systems biology approach used in the present study to investigate the long-term effect of doxorubicin in Saccharomyces cerevisiae cells indicated the up-regulation of genes involved in response to oxidative stress as well as in Rad53 checkpoint sensing and signaling pathway.
Abstract: Doxorubicin is one of the most effective chemotherapy drugs used against solid tumors in the treatment of several cancer types. Two different mechanisms, (i) intercalation of doxorubicin into DNA and inhibition of topoisomerase II leading to changes in chromatin structure, (ii) generation of free radicals and oxidative damage to biomolecules, have been proposed to explain the mode of action of this drug in cancer cells. A genome-wide integrative systems biology approach used in the present study to investigate the long-term effect of doxorubicin in Saccharomyces cerevisiae cells indicated the up-regulation of genes involved in response to oxidative stress as well as in Rad53 checkpoint sensing and signaling pathway. Modular analysis of the active sub-network has also revealed the induction of the genes significantly associated with nucleosome assembly/disassembly and DNA repair in response to doxorubicin. Furthermore, an extensive re-wiring of the metabolism was observed. In addition to glycolysis, and sulfate assimilation, several pathways related to ribosome biogenesis/translation, amino acid biosynthesis, nucleotide biosynthesis, de novo IMP biosynthesis and one-carbon metabolism were significantly repressed. Pentose phosphate pathway, MAPK signaling pathway biological processes associated with meiosis and sporulation were found to be induced in response to long-term exposure to doxorubicin in yeast cells.
TL;DR: Results showed that Que could increase intracellular accumulation of Dox in breast cancer cells through down-regulating the expression of efflux ABC transporters including P-gp, BCRP and MRP1, which can effectively eliminate cancerous cells including breast cancer stem cells (BCSCs).
TL;DR: A tumor could be established in the egg using tumor samples from ovarian cancer patients and that nanoparticles were effective in eliminating the tumor, pointing to the remarkable efficacy of the nanoparticle based drug delivery system.
Abstract: New therapy development is critically needed for ovarian cancer. We used the chicken egg CAM assay to evaluate efficacy of anticancer drug delivery using recently developed biodegradable PMO (periodic mesoporous organosilica) nanoparticles. Human ovarian cancer cells were transplanted onto the CAM membrane of fertilized eggs, resulting in rapid tumor formation. The tumor closely resembles cancer patient tumor and contains extracellular matrix as well as stromal cells and extensive vasculature. PMO nanoparticles loaded with doxorubicin were injected intravenously into the chicken egg resulting in elimination of the tumor. No significant damage to various organs in the chicken embryo occurred. In contrast, injection of free doxorubicin caused widespread organ damage, even when less amount was administered. The lack of toxic effect of nanoparticle loaded doxorubicin was associated with specific delivery of doxorubicin to the tumor. Furthermore, we observed excellent tumor accumulation of the nanoparticles. Lastly, a tumor could be established in the egg using tumor samples from ovarian cancer patients and that our nanoparticles were effective in eliminating the tumor. These results point to the remarkable efficacy of our nanoparticle based drug delivery system and suggests the value of the chicken egg tumor model for testing novel therapies for ovarian cancer.
TL;DR: The evidence published since 2011 confirms that dexrazoxane is an effective cardioprotectant in children and adolescents, is not associated with an increased risk of second primary malignancies or excess early or late mortality and does not impair chemotherapy efficacy.
Abstract: Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of infection, myelosuppression and second primary malignancies, and because its efficacy in children had not then been established. We review here the evidence published since 2011, which confirms that dexrazoxane is an effective cardioprotectant in children and adolescents, is not associated with an increased risk of second primary malignancies or excess early or late mortality and does not impair chemotherapy efficacy. Based on this evidence, the contraindication for children and adolescents requiring high doses of anthracyclines and at risk for cardiotoxicity was removed from the European labeling for dexrazoxane.
TL;DR: An innovative approach to construct a light-activated reactive oxygen species (ROS)-responsive nanoplatform based on a protoporphyrin (PpIX)-conjugated and dual chemotherapeutics-loaded polymer micelle that reverses tumor MDR via the synergism between apatinib-enhanced DOX sensitivity and ROS-mediated PDT performance.
Abstract: Clinical chemotherapy confronts a challenge resulting from cancer-related multidrug resistance (MDR), which can directly lead to treatment failure. To address it, an innovative approach is proposed to construct a light-activated reactive oxygen species (ROS)-responsive nanoplatform based on a protoporphyrin (PpIX)-conjugated and dual chemotherapeutics-loaded polymer micelle. This system combines chemotherapy and photodynamic therapy (PDT) to defeat the MDR of tumors. Such an intelligent nanocarrier can prolong the circulation time in blood because of the negative polysaccharide component of chondroitin sulfate, and subsequently being selectively internalized by MCF-7/ADR cells [doxorubicin (DOX)-resistant]. When exposed to 635 nm red light, this nanoplatform generates sufficient ROS through the photoconversion of PpIX, further triggering the disassociation of the micelles to release the dual cargoes. Afterward, the released apatinib, serving as a reversal inhibitor of MDR, can recover the chemosensitivity...
TL;DR: Thanks to the mediation of Her2 receptor, the specific DOX release and the combination of PDT‐chemotherapy triggered by NIR light, Her2‐I&D‐LSL showed a significant accumulation in MCF7 and SKOV3 tumors, thus leading to the strongest tumor growth inhibition effect.
TL;DR: It is shown that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk, supporting the in vivo relevance of the map of genetic regulation of cellular response to anthracyclines.
Abstract: Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWAS [Formula: see text]-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.
TL;DR: A multifunctional liposome simultaneously loading an oxygen carrier and an anti-tumor drug to enhance chemotherapeutic effects against hypoxic tumors reversed hypoxia-induced chemoresistance and exhibited stronger antitumor effects.
TL;DR: The prepared smart hydrosomal formulation significantly increased the blood half life time of drug and modified the biodistribution and pharmacokinetic parameters of formulated DOX to represent a novel approach in nanomedicine development for effective cancer therapy.
TL;DR: It is speculated that quercetin (Que) reversed MDR in breast cancer cells through downregulating P‐gp expression and eliminating cancer stem cells mediated by YB‐1 nuclear translocation.
Abstract: Overexpression of P-glycoprotein (P-gp) plays an important role in mediating multidrug resistance (MDR), resulting in chemotherapy failure of tumor patients and enhancement of cancer stem cell characteristics. By preparing doxorubicin (Dox) resistant human breast cancer MCF-7 cells, here, we wanted to evaluate the effects of quercetin (Que) on MDR reversal activity and investigate its possible mechanism. MCF-7 and MCF-7/dox cells were respectively treated by Dox, paclitaxel (Pac), or vincristine (Vcr) with or without Que intervention for 24 hr. Cell viability, cell apoptosis, cell cycle, intracellular drug accumulation, the expression of P-gp and Y-box binding protein 1 (YB-1), and breast cancer stem cells (BCSCs) were then assessed. The results showed that Que significantly enhanced the antitumor activities of Dox, Pac, and Vcr in breast cancer cells. In addition, combined treatment of Dox, Pac, or Vcr with Que significantly downregulated P-gp expression and eliminated BCSCs. Furthermore, combined treatment of Dox, Pac, or Vcr with Que significantly inhibited nuclear translocation of YB-1. Thus, we speculated that Que reversed MDR in breast cancer cells through downregulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation.