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Oncology Research Dec 2020Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines,...
Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 2040%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.
Topics: Animals; Anthracyclines; Antineoplastic Agents; Apoptosis; Cardiotoxicity; Cell Line, Tumor; Cell Survival; Doxorubicin; Female; Humans; Maximum Tolerated Dose; Mice; Mice, SCID; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays
PubMed: 32430093
DOI: 10.3727/096504020X15898794315356 -
Biomedicine & Pharmacotherapy =... Aug 2019Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and...
AIM
Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration.
METHODS
The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations.
RESULTS
Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration.
Topics: Animals; Cardiotoxicity; Cell Line; Cell Survival; Doxorubicin; Inhibitory Concentration 50; Male; Metabolome; Rats, Sprague-Dawley
PubMed: 31102935
DOI: 10.1016/j.biopha.2019.108964 -
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 -
Chinese Clinical Oncology Apr 2020While surgical resection is the treatment of choice for adenoid cystic carcinoma (ACC), patients with metastasis and those who cannot undergo surgery receive palliative...
BACKGROUND
While surgical resection is the treatment of choice for adenoid cystic carcinoma (ACC), patients with metastasis and those who cannot undergo surgery receive palliative chemotherapy. However, the role of palliative chemotherapy is not clear yet. This study aimed to evaluate the efficacy of chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) for patients with ACC; and to analyze the relationship between the pre-chemotherapy tumor growth rate (P-TGR) and treatment outcomes in patients with the recurred metastatic unresectable ACC.
METHODS
We retrospectively analyzed the clinical data and treatment outcomes of patients who diagnosed ACC and treated with CAP chemotherapy. Response evaluation was performed using computed tomography (CT) images obtained before and after chemotherapy according to the RECIST 1.1. P-TGR was defined as the difference of the sum of the largest diameter of the target lesion per unit of time between the pre-baseline and baseline CT images.
RESULTS
Fourteen patients with ACC who were treated with CAP were enrolled. Median patient age was 49 years, and the patients received a median of 5 CAP treatment cycles. Two patients achieved partial response (PR) and 10 patients showed stable disease. Response rate was 14.3%, and the disease control rate was 85.7%. Median progression-free survival was 5.7 months (95% CI: 4.3 to not reached) and the median overall survival was 23.4 months (95% CI: 12.9 to not reached). A low P-TGR was associated with a good response to CAP (correlation coefficient, 0.56).
CONCLUSIONS
Palliative CAP chemotherapy demonstrated a modest anti-cancer effect for ACC. A low P-TGR was associated with a good response to CAP chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Adenoid Cystic; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Middle Aged; Retrospective Studies
PubMed: 32366107
DOI: 10.21037/cco.2020.03.07 -
miR-99b-5p, miR-380-3p, and miR-485-3p are novel chemosensitizing miRNAs in high-risk neuroblastoma.Molecular Therapy : the Journal of the... Mar 2022Neuroblastoma is a deadly childhood cancer arising in the developing sympathetic nervous system. High-risk patients are currently treated with intensive chemotherapy,...
Neuroblastoma is a deadly childhood cancer arising in the developing sympathetic nervous system. High-risk patients are currently treated with intensive chemotherapy, which is curative in only 50% of children and leaves some surviving patients with life-long side effects. microRNAs (miRNAs) are critical regulators of neural crest development and are deregulated during neuroblastoma tumorigenesis, making miRNA-based drugs an attractive therapeutic avenue. A functional screen of >1,200 miRNA mimics was conducted in neuroblastoma cell lines to discover miRNAs that sensitized cells to low doses (30% inhibitory concentration [IC]) of doxorubicin and vincristine chemotherapy used in the treatment of the disease. Three miRNAs, miR-99b-5p, miR-380-3p, and miR-485-3p, had potent chemosensitizing activity with doxorubicin in multiple models of high-risk neuroblastoma. These miRNAs underwent genomic loss in a subset of neuroblastoma patients, and low expression predicted poor survival outcome. In vitro functional assays revealed each of these miRNAs enhanced the anti-proliferative and pro-apoptotic effects of doxorubicin. We used RNA sequencing (RNA-seq) to show that miR-99b-5p represses neuroblastoma dependency genes LIN28B and PHOX2B both in vitro and in patient-derived xenograft (PDX) tumors. Luciferase reporter assays demonstrate that PHOX2B is a direct target of miR-99b-5p. We anticipate that restoring the function of the tumor-suppressive miRNAs discovered here may be a valuable therapeutic strategy for the treatment of neuroblastoma patients.
Topics: Child; Doxorubicin; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neuroblastoma
PubMed: 34998954
DOI: 10.1016/j.ymthe.2022.01.004 -
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 -
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 -
PloS One 2022Breast cancer chemotherapy with high dose alkylating agents is severely limited by their collateral toxicity to crucial normal tissues such as immune and gut cells....
BACKGROUND
Breast cancer chemotherapy with high dose alkylating agents is severely limited by their collateral toxicity to crucial normal tissues such as immune and gut cells. Taking advantage of the selective dependence of cancer cells on high glucose and combining glucose deprivation with these agents could produce therapeutic synergy.
METHODS
In this study we examined the effect of glucose as well as its deprivation, and antagonism using the non-metabolized analogue 2-deoxy glucose, on the proliferation of several breast cancer cell lines MCF7, MDA-MB-231, YS1.2 and pII and one normal breast cell line, using the MTT assay. Motility was quantitatively assessed using the wound healing assay. Lactate, as the end product of anaerobic glucose metabolism, secreted into culture medium was measured by a biochemical assay. The effect of paclitaxel and doxorubicin on cell proliferation was tested in the absence and presence of low concentrations of glucose using MTT assay.
RESULTS
In all cell lines, glucose supplementation enhanced while glucose deprivation reduced both their proliferation and motility. Lactate added to the medium could substitute for glucose. The inhibitory effects of paclitaxel and doxorubicin were significantly enhanced when glucose concentration was decreased in the culture medium, requiring 1000-fold lesser concentration to achieve a similar degree of inhibition to that seen in glucose-containing medium.
CONCLUSION
Our data show that a synergy was obtained by combining paclitaxel and doxorubicin with glucose reduction to inhibit cancer cell growth, which in vivo, might be achieved by applying a carbohydrate-restricted diet during the limited phase of application of chemotherapy; this could permit a dose reduction of the cytotoxic agents, resulting in greater tolerance and lesser side effects.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Female; Glucose; Humans; Lactates; Paclitaxel
PubMed: 35917304
DOI: 10.1371/journal.pone.0272449 -
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 -
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