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Cell Death & Disease Dec 2023Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic...
Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic agents. However, most TNBCs acquire resistance to chemotherapy, thereby lowering the therapeutic outcome. In addition to oncogenic mutations in TNBC, microenvironment-induced mechanisms render chemoresistance more complex and robust in vivo. Here, we aimed to analyze whether depletion of Munc18-1 interacting protein 3 (Mint3), which activates hypoxia-inducible factor 1 (HIF-1) during normoxia, sensitizes TNBC to chemotherapy. We found that Mint3 promotes the chemoresistance of TNBC in vivo. Mint3 depletion did not affect the sensitivity of human TNBC cell lines to doxorubicin and paclitaxel in vitro but sensitized tumors of these cells to chemotherapy in vivo. Transcriptome analyses revealed that the Mint3-HIF-1 axis enhanced heat shock protein 70 (HSP70) expression in tumors of TNBC cells. Administering an HSP70 inhibitor enhanced the antitumor activity of doxorubicin in TNBC tumors, similar to Mint3 depletion. Mint3 expression was also correlated with HSP70 expression in human TNBC specimens. Mechanistically, Mint3 depletion induces glycolytic maladaptation to the tumor microenvironment in TNBC tumors, resulting in energy stress. This energy stress by Mint3 depletion inactivated heat shock factor 1 (HSF-1), the master regulator of HSP expression, via the AMP-activated protein kinase/mechanistic target of the rapamycin pathway following attenuated HSP70 expression. In conclusion, Mint3 is a unique regulator of TNBC chemoresistance in vivo via metabolic adaptation to the tumor microenvironment, and a combination of Mint3 inhibition and chemotherapy may be a good strategy for TNBC treatment.
Topics: Humans; Carrier Proteins; Cell Line, Tumor; Doxorubicin; Paclitaxel; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 38081808
DOI: 10.1038/s41419-023-06352-4 -
Pharmacological Research Nov 2023Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However,...
Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.
Topics: Humans; Pharmaceutical Preparations; Neoplasms; Cell Death; Lysosomes; Mitochondria; Erythrocytes; Doxorubicin
PubMed: 37797662
DOI: 10.1016/j.phrs.2023.106945 -
Cancer Medicine Jan 2024Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria...
INTRODUCTION
Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.
METHODS
The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC).
RESULTS
MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival.
CONCLUSION
Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Mitochondrial Dynamics; Cell Line, Tumor; Reactive Oxygen Species; Doxorubicin; Ubiquitin-Protein Ligases; Carcinogenesis; Tumor Microenvironment
PubMed: 38334464
DOI: 10.1002/cam4.6987 -
Breast Cancer Research : BCR Mar 2024Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but...
BACKGROUND
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence.
METHODS
TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated β-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment.
RESULTS
OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro.
CONCLUSION
The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.
Topics: Humans; Histone Deacetylase Inhibitors; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53; Doxorubicin; Apoptosis; RNA, Small Interfering
PubMed: 38429789
DOI: 10.1186/s13058-024-01799-5 -
Journal of Oleo Science Oct 2023In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl...
In this study, we analyzed the properties of amphiphilic alkyldi(methoxy poly(ethylene glycol) (MePEG)350-lactate) phosphates based on ethyl lactate, the monomethyl ether of poly(ethylene glycol)350, and alkyldichloro phosphates. Interestingly, these triesters combine two biodegradable bonds, -P(O)-O-C and -C(O)-O-C-, and include hydrophilic (MePEG350-lactate) and hydrophobic (R-aliphatic chain of alcohols) moieties. The properties of these esters resemble those of phospholipids. After being placed in an aqueous solution, they self-assembled. We also determined the effects of ester composition on micelle formation, stability, and size using dynamic light scattering. Solubilization tests using Sudan III or doxorubicin hydrochloride (Dox·HCl) revealed that they could be incorporated into the hydrophobic cores of dodecyl di(MePEG350-lactate) phosphate and hexadecyl di(MePEG350-lactate) phosphate. Notably, dodecyl di(MePEG350-lactate) phosphate was stable for five days, whereas hexadecyl di(MePEG350-lactate) phosphate was stable for seven days in phosphate-buffered saline. Moreover, Dox·HCl release rates from the micelles were approximately 30-40, 70-80, and 90-100% after 1, 5, and 28 d, respectively.
Topics: Micelles; Polyethylene Glycols; Doxorubicin; Phosphates; Lactates; Drug Carriers
PubMed: 37704442
DOI: 10.5650/jos.ess23108 -
BMC Pharmacology & Toxicology Oct 2023Complications and fata toxicity induced by chemotherapy are the main challenge for clinical management of osteosarcoma. The identification of agents that can augment the...
Complications and fata toxicity induced by chemotherapy are the main challenge for clinical management of osteosarcoma. The identification of agents that can augment the efficacy of chemotherapy at lower doses may represent an alternative therapeutic strategy. Narasin is a polyether antibiotic widely used in veterinary medicine. In this study, we show that narasin is active against osteosarcoma cells at the same concentrations that are less toxic to normal cells. This effect is achieved by growth inhibition and apoptosis induction, which is mediated by oxidative stress and damage, and mitochondrial dysfunction. The antioxidant N-acetyl-l-cysteine (NAC) abolishes the anti-osteosarcoma activity. Importantly, narasin significantly augments doxorubicin's efficacy in both osteosarcoma cell culturing system and subcutaneous implantation mouse model. The combination of narasin and doxorubicin at non-toxic doses completely arrests osteosarcoma growth in mice. Our results suggest that the concurrent administration of doxorubicin and narasin could present a viable alternative therapeutic approach for osteosarcoma.
Topics: Animals; Mice; Osteosarcoma; Doxorubicin; Oxidative Stress; Bone Neoplasms; Cell Line, Tumor; Apoptosis
PubMed: 37864240
DOI: 10.1186/s40360-023-00695-6 -
Electrophoresis Sep 2023As a novel drug delivery system, liposomes were used to improve pharmacokinetics/pharmacodynamics (PK/PD) characters, minimize toxicity, and enhance drug-target...
As a novel drug delivery system, liposomes were used to improve pharmacokinetics/pharmacodynamics (PK/PD) characters, minimize toxicity, and enhance drug-target selectivity. However, heterogeneity of drug releasing process and liposome itself challenged traditional pharmaceutical analytical techniques, especially in vivo pharmacokinetic studies. In this study, a novel liposomal doxorubicin (L-DOX) pharmacokinetic analysis strategy was developed with capillary electrophoresis coupled with laser-induced fluorescence (CE-LIF) detector. The background electrolyte (BGE) system was composed of borate and sodium dodecyl sulfate (SDS), which was optimized to successfully achieve simultaneous online separation and quantitative analysis of free DOX and liposome-encapsulated DOX. The method was applied to the in vivo pharmacokinetic study of L-DOX in rats. The results showed that the concentration of total DOX (T-DOX) was gradually decreasing, while the concentration of L-DOX was relatively stable, with a concentration of 31.6 ± 4.8 µg/mL within 24 h. It was the first time to achieve liposomal drugs in vivo analysis with CE-LIF. CE-LIF was proved as potential rapidly real-time analytical methods for liposomal drugs in vivo occurrence monitoring.
Topics: Rats; Animals; Liposomes; Doxorubicin; Polyethylene Glycols; Electrophoresis, Capillary
PubMed: 37578082
DOI: 10.1002/elps.202300076 -
Advanced Healthcare Materials Dec 2023Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to...
Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to overcome a series of biological and pathological barriers to efficiently kill cancer cells in vivo. Here, this work reports in situ growth of dual-acid-sensitive poly(tertiary amine)-doxorubicin conjugates from albumin to form dual-acid-sensitive albumin-poly(tertiary amine)-doxorubicin conjugates that self-assemble into nanospheres and nanoworms in a controlled manner. Both nanospheres and nanoworms rapidly dissociate into positively-charged unimers at pH < 6.9 and quickly releases the conjugated drug of doxorubicin at pH < 5.6, leading to enhanced penetration in tumor cell spheroids as well as improved uptake and cytotoxicity to tumor cells at pH < 6.9. Notably, nanoworms are less taken up by endothelial cells than nanospheres and doxorubicin, leading to improved pharmacokinetics. In a mouse model of triple negative breast cancer, nanoworms accumulate and penetrate into tumors more efficiently than nanospheres and doxorubicin, leading to enhanced tumor accumulation and penetration. As a result, nanoworms outperform nanospheres and doxorubicin in suppressing tumor growth and elongating the animal survival time, without observed side effects. These findings demonstrate that intelligent nanoworms with spatiotemporally programmed dual-acid-sensitive properties are promising as next-generation nanomedicines for targeted cancer chemotherapy.
Topics: Animals; Mice; Endothelial Cells; Doxorubicin; Drug Delivery Systems; Albumins; Amines; Cell Line, Tumor; Neoplasms
PubMed: 37669689
DOI: 10.1002/adhm.202301890 -
Biomedicine & Pharmacotherapy =... Oct 2023A supramolecular redox responsive nanogel (NG) with the ability to sense cancer cells and loaded with a releasing therapeutic agent was synthesized using hostguest...
A supramolecular redox responsive nanogel (NG) with the ability to sense cancer cells and loaded with a releasing therapeutic agent was synthesized using hostguest interactions between polyethylene glycol-grafted-β-cyclodextrin and ferrocene boronic acid. Cyclic voltammetry matched with other spectroscopy and microscopy methods provided strong indications regarding host-guest interactions and formation of the NG. Moreover, the biological properties of the NG were evaluated using fluorescence silencing, confocal laser scanning microscopy, and cell toxicity assays. Nanogel with spherical core-shell architecture and 100-200 nm sized nanoparticles showed high encapsulation efficiency for doxorubicin (DOX) and luminol (LU) as therapeutic and sensing agents. High therapeutic and sensing efficiencies were manifested by complete release of DOX and dramatic quenching of LU fluorescence triggered by 0.05 mM HO (as an ROS component). The NGs showed high ROS sensitivity. Taking advantage of a high loading capacity, redox sensitivity, and biocompatibility, the NGs can be used as strong theranostic systems in inflammation-associated diseases.
Topics: Precision Medicine; Nanogels; Hydrogen Peroxide; Metallocenes; Reactive Oxygen Species; Doxorubicin; Microscopy, Confocal
PubMed: 37660653
DOI: 10.1016/j.biopha.2023.115402 -
Carbohydrate Polymers Aug 2023Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in...
Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in the treatment of breast cancer. However, the cytotoxicity of DOX has always been an urgent challenge to be solved. In this study, we report an alternative drug delivery system delivering DOX for reducing its physiological toxicity by using the yeast β-glucan particle (YGP) with a hollow and porous vesicle structure. Briefly, amino groups were grafted onto the surface of YGP with the silane coupling agent, then the oxidized hyaluronic acid (OHA) was attached by Schiff base reaction to get HA-modified YGP (YGP@N=C-HA), finally DOX was encapsulated into YGP@N=C-HA to get DOX-loaded YGP@N=C-HA (YGP@N=C-HA/DOX). In vitro release experiments exhibited the pH-responsive DOX release from YGP@N=C-HA/DOX. Cell experiments displayed that YGP@N=C-HA/DOX had good killing effect on both MCF-7 and 4T1 cells and could be internalized into these cells through CD44 receptors, showing targetability to cancer cells. Furthermore, YGP@N=C-HA/DOX could effectively inhibit tumor growth and reduce the physiological toxicity of DOX. Thus, the YGP-based vesicle provides an alternative strategy for lowering the physiological toxicity of DOX in the medical treatment of breast cancer.
Topics: Female; Humans; Breast Neoplasms; Hyaluronic Acid; Saccharomyces cerevisiae; beta-Glucans; Doxorubicin; Drug Delivery Systems; Nanoparticles; MCF-7 Cells
PubMed: 37173014
DOI: 10.1016/j.carbpol.2023.120907