Showing papers on "Doxorubicin published in 2019"

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

Abstract: The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer ( TNBC ) is low1–5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6–13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.

Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy.

Abstract: Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvβ3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

Curcumin Combination Chemotherapy: The Implication and Efficacy in Cancer

Abstract: Many chemotherapeutic drugs have been used for the treatment of cancer, for instance, doxorubicin, irinotecan, 5-fluorouracil, cisplatin, and paclitaxel. However, the effectiveness of chemotherapy is limited in cancer therapy due to drug resistance, therapeutic selectivity, and undesirable side effects. The combination of therapies with natural compounds is likely to increase the effectiveness of drug treatment as well as reduce the adverse outcomes. Curcumin, a polyphenolic isolated from Curcuma longa, belongs to the rhizome of Zingiberaceae plants. Studies from in vitro and in vivo revealed that curcumin exerts many pharmacological activities with less toxic effects. The biological mechanisms underlying the anticancer activity of co-treatment curcumin and chemotherapy are complex and worth to discuss further. Therefore, this review aimed to address the molecular mechanisms of combined curcumin and chemotherapy in the treatment of cancer. The anticancer activity of combined nanoformulation of curcumin and chemotherapy was also discussed in this study. Taken together, a better understanding of the implication and underlying mechanisms of action of combined curcumin and chemotherapy may provide a useful approach to combat cancer diseases.

Aggregable Nanoparticles-Enabled Chemotherapy and Autophagy Inhibition Combined with Anti-PD-L1 Antibody for Improved Glioma Treatment.

Abstract: Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.

Anthracycline‑induced cardiotoxicity in the chemotherapy treatment of breast cancer: Preventive strategies and treatment (Review)

Abstract: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Cardiotoxicity is a well-recognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart failure in some patients. Most experimental data support oxidative stress as the etiology of anthracycline-induced cardiotoxicity. The objective of this paper was to provide a review of the clinical classification, risk factors, monitoring and prevention of anthracycline-induced cardiotoxicity in patients with breast cancer.

Regulation of Ca2+ Signaling for Drug-Resistant Breast Cancer Therapy with Mesoporous Silica Nanocapsule Encapsulated Doxorubicin/siRNA Cocktail

Abstract: Multidrug resistance (MDR) is the key cause that accounts for the failure of clinical cancer chemotherapy. To address the problem, herein, we presented an alternative strategy to conquer drug-resistant breast cancer through the combinatorial delivery of Ca2+ channel siRNA with cytotoxic drugs. Mesoporous silica nanocapsules (MSNCs) with mesoporous and hollow structure were fabricated for co-delivery of T-type Ca2+ channel siRNA and doxorubicin (DOX) with high drug loading efficiency. The DOX/siRNA co-loaded MSNCs showed a synergistic therapeutic effect on drug-resistant breast cancer cells MCF-7/ADR, while had only an additive effect on the drug-sensitive MCF-7 counterpart. It was found that the combination of T-type Ca2+ channel siRNA and DOX had a similar effect on MCF-7 and MCF-7/ADR in the knockdown of overexpressed T-type Ca2+ channels and decrease in cytosolic Ca2+ concentration ([Ca2+]i), but it specifically induced G0/G1 phase cell-cycle arrest and intracellular drug accumulation enhancement in MC...

Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity

Abstract: Importance Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children’s Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin. Objective To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone. Design, Setting, and Participants This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005. Exposures Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records. Main Outcomes and Measures Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories. Results Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model. Conclusions and Relevance In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.

Doxorubicin and Anti-PD-L1 Antibody Conjugated Gold Nanoparticles for Colorectal Cancer Photochemotherapy.

Abstract: Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. The prognosis and overall survival of CRC are known to be significantly correlated with the overexpression of P...

Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency.

Abstract: Doxorubicin is a chemotherapeutic agent that is commonly used to treat a broad range of cancers. However, significant cardiotoxicity, associated with prolonged exposure to doxorubicin, limits its continued therapeutic use. One strategy to prevent the uptake of doxorubicin into cardiac cells is the encapsulation of the drug to prevent non-specific uptake and also to improve the drugs' pharmacokinetic properties. Although encapsulated forms of doxorubicin limit the cardiotoxicity observed, they are not without their own liabilities as an increased amount of drug is deposited in the skin where liposomal doxorubicin can cause palmar-plantar erythrodysesthesia. Exosomes are small endogenous extracellular vesicles, that transfer bioactive material from one cell to another, and are considered attractive drug delivery vehicles due to their natural origin. In this study, we generated doxorubicin-loaded exosomes and demonstrate their rapid cellular uptake and re-distribution of doxorubicin from endosomes to the cytoplasm and nucleus resulting in enhanced potency in a number of cultured and primary cell lines when compared to free doxorubicin and liposomal formulations of doxorubicin. In contrast to other delivery methods for doxorubicin, exosomes do not accumulate in the heart, thereby providing potential for limiting the cardiac side effects and improved therapeutic index.

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment.

Abstract: Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

Abstract: Chemotherapy turns tumor cells into "tumor vaccines" by immunogenic cell death (ICD). However, it remains a challenge to exploit chemotherapy-induced "tumor vaccines" for solid cancer immunotherapy due to the inefficient effector T cells activation and tumor microenvironment immunosuppression. Here, a matrix metalloprotease 2 responsive liposome (PEG-FA-Lip) composed of cleavable PEG chains covering the folate (FA)-modified liposome is developed to deliver ICD inducer doxorubicin. In breast cancer-bearing mice, PEG-FA-Lip targets both 4T1 breast cancer cells and M2-tumor associated macrophages (M2-TAMs) via FA-receptor mediated endocytosis, resulting in abundant "tumor vaccines" and efficient elimination of M2-TAMs. The combination of local cytosine-phosphate-guanine (CpG) therapy facilitates PEG-FA-Lip induced "tumor vaccines" to effectively arouse systematic effector T cells immune response through promoting dendritic cell maturation and immunostimulatory cytokines secretion. The simultaneous elimination of M2-TAMs ensures the activated effector T cells exert antitumor immunity within tumor via decreasing immunosuppressive cytokines secretion and tumor infiltration of Treg cells. After receiving the combined treatment, 30.1% of breast cancer-bearing mice (initial tumor volume > 100 mm3) achieves the goal of tumor eradication. Remarkably, this combination therapy greatly inhibits lung metastasis and controls the growth of already metastasized breast cancers (initial tumor volume > 100 mm3).

Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity.

Abstract: AIMS Combined administration of anthracyclines (e.g. doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2), is an effective treatment for HER2-positive breast cancer. However, both agents are associated with cardiac toxicity. Human cardiac-resident mesenchymal progenitor cells (CPCs) secrete extracellular vesicles including nanosized exosomes which protect against myocardial ischaemia. Here, we investigated the effects of these exosomes using a novel model of Dox/Trz-mediated cardiotoxicity. METHODS AND RESULTS CPCs were derived from cardiac atrial appendage specimens from patients who underwent heart surgery for heart valve disease and/or ischaemic heart disease, and exosomes were purified from CPC conditioned media. Proteomics analyses revealed that CPC exosomes contained multiple proteins involved in redox processes. Dox/Trz induced a significant increase in reactive oxygen species (ROS) in rat cardiomyocytes, which was prevented by CPC exosomes. In vivo, rats received six doses of Dox (Days 1-11), followed by six doses of Trz (Days 19-28). Three doses of either exosomes or exosome suspension vehicle were injected intravenously on Days 5, 11, and 19 in the treatment and control groups, respectively. Dox/Trz induced myocardial fibrosis, CD68+ inflammatory cell infiltrates, inducible nitric oxide synthase expression, and left ventricular dysfunction. CPC exosomes prevented these effects. These vesicles were highly enriched in miR-146a-5p compared with human dermal fibroblast exosomes. Dox upregulated Traf6 and Mpo, two known miR-146a-5p target genes (which encode signalling mediators of inflammatory and cell death axes) in myocytes. CPC exosomes suppressed miR-146a-5p target genes Traf6, Smad4, Irak1, Nox4, and Mpo in Dox-treated cells. Specific silencing of miR-146a-5p abrogated exosome-mediated suppression of those genes leading to an increase in Dox-induced cell death. CONCLUSIONS Human CPC exosomes attenuate Dox-/Trz-induced oxidative stress in cardiomyocytes. Systemic administration of these vesicles prevents Dox/Trz cardiotoxicity in vivo. miR-146a-5p mediates some of the benefits of exosomes in this setting.

Doxorubicin-loaded nanoscale metal-organic framework for tumor-targeting combined chemotherapy and chemodynamic therapy.

Abstract: Doxorubicin (DOX) as a traditional chemotherapy drug is restricted in clinical applications due to its poor therapeutic activity and severe side effects. Herein, we prepared a metal–organic framework (MOF) MIL-100 by a microwave-assisted synthesis and DOX was loaded in MIL-100 and then, hyaluronic acid (HA) was modified on the surface of MIL-100 to give DMH NPs. The DMH NPs possessed the following advantages: (1) MIL-100 could serve as a drug carrier with a high DOX loading efficiency; MIL-100 could also generate a hydroxyl radical (˙OH) in the presence of H2O2 for chemodynamic therapy (CDT) via a Fenton-like reaction. (2) To improve the dispersibility of MIL-100, HA was modified on the surface of MIL-100, which could endow MIL-100 with a targeting ability towards tumor tissues. (3) DMH NPs could enhance antitumor efficacy and reduce drug-related toxicity though the combination of chemotherapy and chemodynamic therapy. DMH NPs have enormous potential as a candidate for reducing the systemic toxicity and improving the treatment effect for breast cancer.

Photothermal-Chemotherapy Integrated Nanoparticles with Tumor Microenvironment Response Enhanced the Induction of Immunogenic Cell Death for Colorectal Cancer Efficient Treatment

Abstract: Inducing immunogenic cell death (ICD) that enhances the immunogenicity of dead cancer cells is a new strategy for tumor immunotherapy, but efficiently triggering ICD is the biggest obstacle to achieving this strategy, especially for distant and deep-seated tumors. Here, a new therapeutic system (Pd-Dox@TGMs NPs) that can effectively trigger ICD by combining chemotherapy and photothermal therapy was designed. The nanosystem was fabricated by integrating doxorubicin (Dox) and a photothermal reagent palladium nanoparticles (Pd NPs) into amphiphile triglycerol monostearates (TGMs), which showed specific accumulation, deep penetration, and activation in response to the tumoral enzymatic microenvironment. It was proved that codelivery of Dox and Pd NPs not only effectively killed CT26 cells through chemotherapy and photothermal therapy but also promoted the release of dangerous signaling molecules, such as high mobility group box 1, calreticulin, and adenosine triphosphate, improving the immunogenicity of dead tumor cells. The effective ICD induction mediated by Pd-Dox@TGMs NPs boosted the PD-L1 checkpoint blockade effect, which efficiently improved the infiltration of toxic T lymphocytes at the tumor site and showed excellent tumor treatment effects to both primary and abscopal tumors. Therefore, this work provides a simple and effective immunotherapeutic strategy by combining chemical-photothermal therapy to enhance immune response.

Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP)

Abstract: Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.

Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model.

Abstract: Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. It has, however, been shown that doxorubicin can induce drug resistance resulting in poor patient prognosis and survival. Studies reported that the interaction between signalling pathways can promote drug resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis. The aim of this study was therefore to determine the effects of doxorubicin on apoptosis signalling, autophagy, the mitogen-activated protein kinase (MAPK)- and phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, cell cycle control, and regulators of the epithelial-mesenchymal transition (EMT) process in murine breast cancer tumours. A tumour-bearing mouse model was established by injecting murine E0771 breast cancer cells, suspended in Hank’s Balances Salt Solution and Corning® Matrigel® Basement Membrane Matrix, into female C57BL/6 mice. Fourty-seven mice were randomly divided into three groups, namely tumour control (received Hank’s Balances Salt Solution), low dose doxorubicin (received total of 6 mg/ml doxorubicin) and high dose doxorubicin (received total of 15 mg/ml doxorubicin) groups. A higher tumour growth rate was, however, observed in doxorubicin-treated mice compared to the untreated controls. We therefore compared the expression levels of markers involved in cell death and survival signalling pathways, by means of western blotting and fluorescence-based immunohistochemistry. Doxorubicin failed to induce cell death, by means of apoptosis or autophagy, and cell cycle arrest, indicating the occurrence of drug resistance and uncontrolled proliferation. Activation of the MAPK/ extracellular-signal-regulated kinase (ERK) pathway contributed to the resistance observed in treated mice, while no significant changes were found with the PI3K/Akt pathway and other MAPK pathways. Significant changes were also observed in cell cycle p21 and DNA replication minichromosome maintenance 2 proteins. No significant changes in EMT markers were observed after doxorubicin treatment. Our results suggest that doxorubicin-induced drug resistance and tumour growth can occur through the adaptive role of the MAPK/ERK pathway in an effort to protect tumour cells. Previous studies have shown that the efficacy of doxorubicin can be improved by inhibition of the ERK signalling pathway and thereby treatment failure can be overcome.

Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro.

Abstract: Eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has been shown to play an important role in modulating autophagy and apoptosis in tumor cells under various stresses. In this study, we investigated the regulatory role of eEF-2K in pyroptosis (a new form of programmed necrosis) in doxorubicin-treated human melanoma cells. We found that doxorubicin (0.5-5 μmol/L) induced pyroptosis in melanoma cell lines SK-MEL-5, SK-MEL-28, and A-375 with high expression of DFNA5, but not in human breast cancer cell line MCF-7 with little expression of DFNA5. On the other hand, doxorubicin treatment activated autophagy in the melanoma cells; inhibition of autophagy by transfecting the cells with siRNA targeting Beclin1 or by pretreatment with chloroquine (20 μmol/L) significantly augmented pyroptosis, thus sensitizing the melanoma cells to doxorubicin. We further demonstrated that doxorubicin treatment activated eEF-2K in the melanoma cells, and silencing of eEF-2K blunted autophagic responses, but promoted doxorubicin-induced pyroptotic cell death. Taken together, the above results demonstrate that eEF-2K dictates the cross-talk between pyroptosis and autophagy in doxorubicin-treated human melanoma cells; suppression of eEF-2K results in inhibiting autophagy and augmenting pyroptosis, thus modulating the sensitivity of melanoma cells to doxorubicin, suggesting that targeting eEF-2K may reinforce the antitumor efficacy of doxorubicin, offering a new insight into tumor chemotherapy.

Combretastatin A4 Nanodrug-Induced MMP9 Amplification Boosts Tumor-Selective Release of Doxorubicin Prodrug

Abstract: Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.

Embryonic stem cell-derived exosomes inhibit doxorubicin-induced TLR4-NLRP3-mediated cell death-pyroptosis

Abstract: Doxorubicin (Dox)-induced cardiotoxicity is mediated through increased oxidative stress, apoptosis, and necrosis. We report for the first time as per the best of our knowledge that Dox initiates To...

Galactose-modified selenium nanoparticles for targeted delivery of doxorubicin to hepatocellular carcinoma

Abstract: Galactose-modified selenium nanoparticles (GA-SeNPs) loading with doxorubicin (DOX) for hepatocellular carcinoma (HCC) therapy was investigated in this paper. Selenium nanoparticles (SeNPs) were modified with galactose as tumor targeting moiety to fabricate tumor-targeted delivery carrier GA-SeNPs, then doxorubicin was loaded onto the surface of GA-SeNPs for improving antitumor efficacy of DOX in HCC therapy. Chemical structure characterization of GA-Se@DOX showed that DOX was successfully loaded to the surface of GA-SeNPs to prepare functionalized antitumor drug delivery system GA-Se@DOX. GA-Se@DOX exhibited effective cellular uptake in HepG2 cells and entered HepG2 cells mainly by clathrin-mediated endocytosis pathway. GA-Se@DOX showed significant activity to induce the apoptosis of HepG2 cells in vitro. The western blotting result indicated that GA-Se@DOX induced HepG2 cells apoptosis via activating caspase signaling and Bcl-2 family proteins. Moreover, active targeting delivery system GA-Se@DOX exhibited excellent antitumor efficacy in vivo in comparison with passive targeting delivery system Se@DOX. Histology analysis showed that GA-Se@DOX exhibited no obvious damage to major organs including heart, liver, spleen, lung, and kidney under the experimental condition. Taken together, GA-Se@DOX may be one novel promising nanoscale drug candidate for HCC therapy.

Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells

Abstract: In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.

GRP78-targeted ferritin nanocaged ultra-high dose of doxorubicin for hepatocellular carcinoma therapy

Abstract: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer deaths, primarily due to its high incidence of recurrence and metastasis. Considerable efforts have therefore been undertaken to develop effective therapies; however, effective anti-HCC therapies rely on identification of suitable biomarkers, few of which are currently available for drug targeting. Methods: GRP78 was identified as the membrane receptor of HCC-targeted peptide SP94 by immunoprecipitation and mass spectrum analysis. To develop an effective anti-HCC drug nanocarrier, we first displayed GRP78-targeted peptide SP94 onto the exterior surface of Pyrococcus furiosus ferritin Fn (HccFn) by genetic engineering approach, and then loaded doxorubicin (Dox) into the cavities of HccFn via urea-based disassembly/reassembly method, thereby constructing a drug nanocarrier called HccFn-Dox. Results: We demonstrated that HccFn nanocage encapsulated ultra-high dose of Dox (up to 400 molecules Dox/protein nanocage). In vivo animal experiments showed that Dox encapsulated in HccFn-Dox was selectively delivered into HCC tumor cells, and effectively killed subcutaneous and lung metastatic HCC tumors. In addition, HccFn-Dox significantly reduced drug exposure to healthy organs and improved the maximum tolerated dose by six-fold compared with free Dox. Conclusion: In conclusion, our findings clearly demonstrate that GRP78 is an effective biomarker for HCC therapy, and GRP78-targeted HccFn nanocage is effective in delivering anti-HCC drug without damage to healthy tissue.

Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Abstract: Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER−) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however, there is no formal evidence for it. Here, we provide experimental evidence that ER− breast cancer cells that survived high-dose Doxorubicin and Methotrexate based chemotherapies elicit a state of immunological dormancy. Hallmark of this dormant phenotype is the sustained activation of the IRF7/IFN-β/IFNAR axis subsisting beyond chemotherapy treatment. Upregulation of IRF7 in treated cancer cells promoted resistance to chemotherapy, reduced cell growth and induced switching of the response from a myeloid derived suppressor cell-dominated immune response to a CD4+/CD8+ T cell-dependent anti-tumor response. IRF7 silencing in tumor cells or systemic blocking of IFNAR reversed the state of dormancy, while spontaneous escape from dormancy was associated with loss of IFN-β production. Presence of IFN-β in the circulation of ER− breast cancer patients treated with neoadjuvant Epirubicin chemotherapy correlated with a significantly longer distant metastasis-free survival. These findings establish chemotherapy-induced immunological dormancy in ER− breast cancer as a novel concept for (neo)adjuvant chemotherapy activity, and implicate sustained activation of the IRF7/IFN-β/IFNAR pathway in this effect. Further, IFN-β emerges as a potential predictive biomarker and therapeutic molecule to improve outcome of ER− breast cancer patients treated with (neo)adjuvant chemotherapy.

pH Responsiveness of Hexosomes and Cubosomes for Combined Delivery of Brucea javanica Oil and Doxorubicin.

Abstract: We report pH-responsive liquid crystalline lipid nanoparticles, which are dual-loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH = 7.4) to cubic (pH = 6.8) to emulsified microemulsion (pH = 5.3) phase transition with a therapeutic application in cancer inhibition. BJO is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an antitumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need for safe delivery carriers. Here, pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein-oleic acid-BJO-DOX) systems are determined by synchrotron small-angle X-ray scattering and the Langmuir film balance technique. The nanocarrier assemblies display good physical stability in the studied pH range and adequate particle sizes and ζ-potentials. Their interaction with model lipid membrane interfaces is enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO-DOX dual-loaded pH-switchable liquid crystalline nanoparticles are performed on the human breast cancer Michigan Cancer Foundation-7 (MCF-7) cell line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines exhibit enhanced antitumor efficacy. The performed preliminary studies suggest a potential reversal of the resistance of the MCF-7/DOX cells to DOX. These results highlight the necessity for further understanding the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, and emulsified microemulsion inner organizations for therapeutic outcomes.