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Asian Pacific Journal of Cancer... Dec 2022Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and...
BACKGROUNDS
Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and therapeutic resistance ability. Quercetin is a popular flavonoid with lower adverse effects and has anti-tumor properties. Therefore, we assessed the anticancer activity of Quercetin and Doxorubicin alone and in combination in the T47D cells of human breast cancer and their isolated Cancer stem cells (CSCs).
MATERIALS AND METHODS
The human breast cancer cell line T47D was used for this experiment. T47D CSCs were isolated by magnetic bead sorting using the MACS system. The anticancer activity of Quercetin and Doxorubicin alone and in combination were evaluated using MTT cytotoxicity assay and cell cycle distribution and apoptosis induction by flow cytometry analysis.
RESULTS
We have shown that almost 1% of T47D cell populations are made up of CD44+/CD24- cells, which considered as cancer stem cells. Quercetin and Doxorubicin alone or in combination inhibited cell proliferation and induced apoptosis in breast cancer T47D cells and in lower extent in CD44+/CD24- cells. Quercetin significantly strengthened Doxorubicin's cytotoxicity and apoptosis induction in both cell populations. Quercetin and Doxorubicin and their combination induced G2/M arrest in the T47D cells and to a lesser extent in isolated CSCs. A value of p < 0.05 was considered as indicating a statistically significant difference.
CONCLUSION
These outcomes suggested that CSCs are a minor population of cancer cells, which play a significant role in drug resistance by being quiescent, slow cycling and resistance to apoptosis. Furthermore, our data showed that adding Quercetin to Doxorubicin is an effective approach for the treatment of both CSCs and bulk tumor cells.
Topics: Humans; Female; Quercetin; Apoptosis; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; Doxorubicin; Cell Cycle Checkpoints; Breast Neoplasms; Cell Proliferation; Cell Cycle; Neoplastic Stem Cells
PubMed: 36579996
DOI: 10.31557/APJCP.2022.23.12.4145 -
Cancer Chemotherapy and Pharmacology Mar 2022Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the... (Review)
Review
Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the mechanistic details of its cytotoxic action remain controversial. Rather than one key mechanism of cytotoxic action, DOX is characterized by multiple mechanisms, such as (1) DNA intercalation and adduct formation, (2) topoisomerase II (TopII) poisoning, (3) the generation of free radicals and oxidative stress, and (4) membrane damage through altered sphingolipid metabolism. Many past reviews of DOX cytotoxicity are based on supraclinical concentrations, and several have addressed the concentration dependence of these mechanisms. In addition, most reviews lack a focus on the time dependence of these processes. We aim to update the concentration and time-dependent trends of DOX mechanisms at representative clinical concentrations. Furthermore, attention is placed on DOX behavior in breast cancer cells due to the frequent use of DOX to treat this disease. This review provides insight into the mechanistic pathway(s) of DOX at levels found within patients and establishes the magnitude of effect for each mechanism.
Topics: Antineoplastic Agents; Breast Neoplasms; DNA Topoisomerases, Type II; Doxorubicin; Female; Humans; Oxidative Stress
PubMed: 35150291
DOI: 10.1007/s00280-022-04400-y -
Photochemistry and Photobiology Mar 2023Porphyrin-phospholipid (PoP) liposomes loaded with Doxorubicin (Dox) have been demonstrated to be an efficient vehicle for chemophototherapy (CPT). Multidrug resistance... (Review)
Review
Porphyrin-phospholipid (PoP) liposomes loaded with Doxorubicin (Dox) have been demonstrated to be an efficient vehicle for chemophototherapy (CPT). Multidrug resistance (MDR) of cancer cells is a problematic phenomenon in which tumor cells develop resistance to chemotherapy. Herein, we report that Dox-resistant tumor cells can be ablated using our previously described formulation termed long-circulating Dox loaded in PoP liposomes (LC-Dox-PoP), which is a PEGylated formulation containing 2 mol. % of the PoP photosensitizer. In vitro studies using free Dox and LC-Dox-PoP showed that human ovarian carcinoma A2780 cells were more susceptible to Dox compared to the corresponding Dox-resistant A2780-R cells. When CPT was applied with LC-Dox-PoP liposomes, effective killing of both nonresistant and resistant A2780 cell lines was observed. An in vivo study to assess the efficiency of LC-Dox-PoP showed effective tumor shrinkage and prolonged survival of athymic nude mice bearing subcutaneous Dox-resistant A2780-R tumor xenografts when they were irradiated with a red laser. Biodistribution analysis demonstrated enhanced tumoral drug uptake in Dox-resistant tumors with CPT, suggesting that increased drug delivery was sufficient to induce ablation of resistant tumor cells.
Topics: Mice; Animals; Humans; Female; Liposomes; Ovarian Neoplasms; Cell Line, Tumor; Mice, Nude; Tissue Distribution; Doxorubicin; Phospholipids
PubMed: 35842741
DOI: 10.1111/php.13677 -
ACS Sensors Jun 2023Understanding the dynamics and distribution of medicinal drugs in living cells is essential for the design and discovery of treatments. The tools available for revealing...
Understanding the dynamics and distribution of medicinal drugs in living cells is essential for the design and discovery of treatments. The tools available for revealing this information are, however, extremely limited. Here, we report the application of surface-enhanced Raman scattering (SERS) endoscopy, using plasmonic nanowires as SERS probes, to monitor the intracellular fate and dynamics of a common chemo-drug, doxorubicin, in A549 cancer cells. The unique spatio-temporal resolution of this technique reveals unprecedented information on the mode of action of doxorubicin: its localization in the nucleus, its complexation with medium components, and its intercalation with DNA as a function of time. Notably, we were able to discriminate these factors for the direct administration of doxorubicin or the use of a doxorubicin delivery system. The results reported here show that SERS endoscopy may have an important future role in medicinal chemistry for studying the dynamics and mechanism of action of drugs in cells.
Topics: Humans; Pharmaceutical Preparations; Doxorubicin; Antineoplastic Agents; Endoscopy; Neoplasms
PubMed: 37219991
DOI: 10.1021/acssensors.3c00394 -
Canadian Journal of Physiology and... Feb 2021Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system....
Doxorubicin is an anticancer agent that is commonly used to treat a number of tumors and is associated with acute and chronic changes of the cardiovascular system. Ellagic acid has strong free radical scavenging capacity, neuroprotective and hepatoprotective effects, and is known to protect against changes occurring due to diabetes, cardiovascular diseases, and cancer. Twenty-four Wistar rats were divided in four groups: control group received saline, doxorubicin group received doxorubicin in a single dose of 20 mg/kg, ellagic acid group received ellagic acid in a dose of 4 mg/kg, and doxorubicin + ellagic acid group received doxorubicin and ellagic acid in same doses as in previous groups. The effect of ellagic acid treatment, alone or in combination with doxorubicin, was studied on isolated heart frequency and strength of the contraction, and on thoracic aorta contractile responses. Application of ellagic acid to rats pre-treated with doxorubicin significantly prevented functional changes occurring in the heart, but not in the thoracic aorta tissue. Ellagic acid statistically significantly ( < 0.001) prevented doxorubicin-induced increase in heart rate, while at the same time increased single contraction force ( < 0.001) and attenuated morphological changes on heart tissue induced by doxorubicin. We can conclude that ellagic acid has potential to prevent doxorubicin-induced changes of the cardiovascular system.
Topics: Animals; Cytoprotection; Dose-Response Relationship, Drug; Doxorubicin; Ellagic Acid; Heart; Male; Rats; Rats, Wistar
PubMed: 33509026
DOI: 10.1139/cjpp-2020-0404 -
The Journal of Pharmacy and Pharmacology Jun 2016The use of doxorubicin, a drug utilised for many years to treat a wide variety of cancers, has long been limited due to the significant toxicity that can occur not only... (Review)
Review
OBJECTIVES
The use of doxorubicin, a drug utilised for many years to treat a wide variety of cancers, has long been limited due to the significant toxicity that can occur not only during, but also years after treatment. It has multiple mechanisms of action including the intercalation of DNA, inhibition of topoisomerase II and the production of free radicals. We review the literature, with the aim of highlighting the role of drug concentration being an important determinant on the unfolding cell biological events that lead to cell stasis or death.
METHODS
The PubMed database was consulted to compile this review.
KEY FINDINGS
It has been found that the various mechanisms of action at the disposal of doxorubicin culminate in either cell death or cell growth arrest through various cell biological events, such as apoptosis, autophagy, senescence and necrosis. Which of these events is the eventual cause of cell death or growth arrest appears to vary depending on factors such as the patient, cell and cancer type, doxorubicin concentration and the duration of treatment.
CONCLUSIONS
Further understanding of doxorubicin's influence on cell biological events could lead to an improvement in the drug's efficacy and reduce toxicity.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Autophagy; Cell Proliferation; Cellular Senescence; Dose-Response Relationship, Drug; Doxorubicin; Energy Metabolism; Humans; Necrosis; Neoplasms; Time Factors; Topoisomerase II Inhibitors
PubMed: 26989862
DOI: 10.1111/jphp.12539 -
ACS Nano Jun 2023The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated...
The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated antigens (TAAs) and damage-associated molecule patterns. However, doxorubicin (DOX)-induced tumor-specific T-cell-mediated immune response is usually very weak because of antigen presentation deficiency and the immunosuppressive tumor microenvironment (ITME). Herein, the probiotic (Bi) was covalently modified with DOX-loaded CaP/SiO nanoparticles (DNPs@Bi) for tumor therapy. On one hand, the pH-responsive release of DOX could induce chemotherapy and ICD in the ITME. On the other hand, tumor-targeting Bi is able to significantly enhance the presentation of TAAs from B16F10 cells to DCs Cx43-dependent gap junctions. Due to the combination of enhanced ICD and TAAs presentation, the maturation of DCs and the infiltration of cytotoxic T lymphocytes in the ITME were stimulated. As a result, antitumor experiments demonstrated that DNPs@Bi prolonged the survival rate and significantly inhibited the tumor progression and metastasis. This strategy of bacterial-driven hypoxia-targeting delivery systems offers a promising approach to tumor chemo-immunotherapy.
Topics: Humans; Bifidobacterium bifidum; Antigen Presentation; Immunogenic Cell Death; Silicon Dioxide; Doxorubicin; Neoplasms; Nanoparticles; Antigens, Neoplasm; Immunotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37212750
DOI: 10.1021/acsnano.2c11474 -
International Journal of Biological... Apr 2023Alginate (AL), in the form of a hydrogel, is extensively used in drug delivery. In the current study, an optimum formulation of alginate-coated niosome-based...
Alginate (AL), in the form of a hydrogel, is extensively used in drug delivery. In the current study, an optimum formulation of alginate-coated niosome-based nanocarriers for co-delivery of doxorubicin (Dox) and cisplatin (Cis) was obtained for the treatment of breast and ovarian cancers in an attempt to decrease drug doses and overcome multidrug resistance. The physiochemical characteristics of uncoated niosomes containing Cis and Dox (Nio-Cis-Dox) compared to alginate-coated niosomes formulation (Nio-Cis-Dox-AL). The three-level Box-Behnken method was examined to optimize the particle size, polydispersity index, entrapment efficacy (%), and percent drug release of nanocarriers. Nio-Cis-Dox-AL showed appropriate encapsulation efficiencies of 65.54 ± 1.25 % and 80.65 ± 1.80 % for Cis and Dox, respectively. Maximum drug release decreased from niosomes in case coated by alginate. Also, the zeta potential value of Nio-Cis-Dox nanocarriers decreased after coating with alginate. In vitro cellular and molecular experiments were performed to investigate the anticancer activity of Nio-Cis-Dox and Nio-Cis-Dox-AL. MTT assay showed the IC of Nio-Cis-Dox-AL was much lower than the Nio-Cis-Dox formulations and free drugs. Cellular and molecular assays demonstrated that Nio-Cis-Dox-AL caused significant increase in apoptosis induction rate and cell cycle arrest in MCF-7 and A2780 cancer cells, as compared to Nio-Cis-Dox and free drugs. Also, the Caspase 3/7 activity increased after treatment with coated niosomes compared to uncoated nisomes and the drug-free case. Synergetic cell proliferation inhibitory impacts of Cis and Dox were demonstrated against MCF-7 and A2780 cancer cells. All anticancer experimental data demonstrated that the co-delivery of Cis and Dox through alginate-coated niosomal nanocarriers was effective for ovarian and breast cancer treatment.
Topics: Humans; Female; Liposomes; Cisplatin; Cell Line, Tumor; Alginates; Ovarian Neoplasms; Doxorubicin
PubMed: 36801304
DOI: 10.1016/j.ijbiomac.2023.123686 -
Toxicology Letters Dec 2015The anticancer drug doxorubicin and its liposomal formulations are in clinical use, doxorubicin also during pregnancy. However, little is known about how doxorubicin and...
The anticancer drug doxorubicin and its liposomal formulations are in clinical use, doxorubicin also during pregnancy. However, little is known about how doxorubicin and its liposomal formulations are taken up by placental cells and whether they can cross human placenta. We therefore investigated quantitative cellular uptake and toxicity of doxorubicin and its two liposomal formulations, pH-sensitive liposomal doxorubicin (L-DOX) and commercially available pegylated liposomal doxorubicin (PL-DOX), in human placental choriocarcinoma (BeWo) cells. PL-DOX showed significantly lower cellular uptake and toxicity compared with doxorubicin and L-DOX. In preliminary studies with human placental perfusion, PL-DOX did not cross the placenta at all in 4h, whereas doxorubicin and L-DOX crossed the placenta at low levels (max 12% of the dose). Furthermore, PL-DOX did not accumulate in placental tissue while doxorubicin did (up to 70% of the dose). Surface pegylation probably explains the low placental cell and tissue uptake of PL-DOX. Formulation of doxorubicin thus seems to enable a decrease of fetal exposure.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Survival; Doxorubicin; Female; Humans; Liposomes; Placenta; Pregnancy
PubMed: 26383631
DOI: 10.1016/j.toxlet.2015.09.011 -
Nano Letters Nov 2023Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane...
Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane nanodelivery system (designated as PMNPs-D) to simultaneously target CAFs and tumor cells for boosted chemotherapy through promoted drug perfusion. In the structure of PMNPs-D, the PLGA-based inner core is loaded with the chemotherapeutic drug doxorubicin, and the outer surface is cloaked by hybrid biomembranes with the insertion of integrin β1 (ITGB1) inhibiting peptide (i.e., FNIII14). After prolonged blood circulation and actively targeting in tumor sites, PMNPs-D can respond to CAF-overexpressed fibroblast activation protein-α (FAP-α) to trigger the release of FNIII14, which will bind to ITGB1 and inhibit CAFs' biological function in producing the stromal matrix, thereby loosening the condensed stromal structure and enhancing the permeability of nanotherapeutics in tumors. As a result, this tailor-designed nanosystem shows substantial tumor inhibition and metastasis retardation in aggressive adenoid cystic carcinoma (ACC) tumor-harboring mice.
Topics: Animals; Mice; Cancer-Associated Fibroblasts; Neoplasms; Doxorubicin; Membranes; Peptides; Tumor Microenvironment; Cell Line, Tumor; Fibroblasts
PubMed: 37729438
DOI: 10.1021/acs.nanolett.3c02983