-
Biology Direct Jun 2024Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have...
BACKGROUND
Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML.
METHODS
In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML.
RESULTS
We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells.
CONCLUSIONS
Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.
Topics: Leukemia, Myeloid, Acute; Humans; HMGA2 Protein; MicroRNAs; Drug Resistance, Neoplasm; Doxorubicin; RNA, Long Noncoding; Mice; Animals; Cell Line, Tumor; HL-60 Cells; Gene Silencing; Apoptosis; Cell Proliferation; Female
PubMed: 38910243
DOI: 10.1186/s13062-024-00490-1 -
Medical Oncology (Northwood, London,... Jun 2024The purpose of the present study was in vitro determination of the combined effects of doxorubucin and 5-fluorouracil by 2D and 3D culture conditions on breast cancer...
The purpose of the present study was in vitro determination of the combined effects of doxorubucin and 5-fluorouracil by 2D and 3D culture conditions on breast cancer using MCF-7 cell line and CSCs isolated from these cells. In the first stage of this study, CSC isolation and their characterization were performed. In the next experimental period, the antiproliferative effects of 5-Fu and Dox on the MCF-7 and CSCs were demonstrated on 2D. To evaluate the synergistic/antagonistic effects of these chemotherapeutics, the CI was calculated. Additionally, 3D tumor spheroids were used as another model. In the last step, qRT-PCR analysis was performed to examine apoptosis-related gene expressions. In this study, it was clearly seen that CSCs obtained from the breast cancer cell line express stemness factors. In addition, the antiproliferative effects of 5-Fu and Dox on breast cancer and associated CSCs were very clear. Their synergistic effects were determined by CI values. Moreover, it was seen that combined theraphy changed the expression levels of genes related to apoptosis. Additionally, it was molecularly demonstrated that 3D tumoroids were more resistant than the others. In conclusion, the polychemotherapeutic approach was much more effective than the monotherapy. The fact that this effect was seen not only in breast cancer cells, but also in breast cancer stem cells. In addition, it was very promising that the results obtained were similar in both two-dimensional and three-dimensional tumoroids.
Topics: Humans; Fluorouracil; Neoplastic Stem Cells; Doxorubicin; Breast Neoplasms; Female; MCF-7 Cells; Spheroids, Cellular; Apoptosis; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Drug Synergism
PubMed: 38910198
DOI: 10.1007/s12032-024-02423-4 -
Journal of Nanobiotechnology Jun 2024Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful...
Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms.
Topics: Tumor Microenvironment; Animals; Immunotherapy; Doxorubicin; Humans; Mice; Cell Line, Tumor; Female; Mice, Inbred BALB C; Nanoparticles; Breast Neoplasms; Gene Editing; CRISPR-Cas Systems; Manganese Compounds; Drug Resistance, Neoplasm; Drug Delivery Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Antineoplastic Agents; Oxides
PubMed: 38898493
DOI: 10.1186/s12951-024-02571-9 -
Molecules (Basel, Switzerland) Jun 2024Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores...
Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.
Topics: Humans; Apigenin; Doxorubicin; Breast Neoplasms; Female; Cell Line, Tumor; Cell Survival; MCF-7 Cells; Cell Movement; Signal Transduction; Cell Proliferation; Drug Synergism
PubMed: 38893482
DOI: 10.3390/molecules29112603 -
Molecules (Basel, Switzerland) May 2024Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is...
Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is effective and universal; however, it also causes numerous side effects. The most serious of them are cardiotoxicity and a decrease in the number of myeloid cells. For this reason, targeted DOX delivery systems are desirable, since they would allow lowering the drug dose and therefore limiting systemic side effects. Recently, synthetic dyes, in particular Congo red (CR), have been proposed as possible DOX carriers. CR is a planar molecule, built of a central biphenyl moiety and two substituted naphthalene rings, connected with diazo bonds. In water, it forms elongated ribbon-shaped supramolecular structures, which are able to selectively interact with immune complexes. In our previous studies, we have shown that CR aggregates can intercalate DOX molecules. In this way, they preclude DOX precipitation in water solutions and increase its uptake by MCF7 breast cancer cells. In the present work, we further explore the interactions between DOX, CR, and their aggregates (CR/DOX) with phospholipid membranes. In addition to neutral molecules, the protonated doxorubicin form, DXP, is also studied. Molecular dynamics simulations are employed to study the transfer of CR, DOX, DXP, and their aggregates through POPC bilayers. Interactions of CR, DOX, and CR/DOX with model monolayers are studied with Langmuir trough measurements. This study shows that CR may support the transfer of doxorubicin molecules into the bilayer. Both electrostatic and van der Waals interactions with lipids are important in this respect. The former promote the initial stages of the insertion process, the latter keep guest molecules inside the bilayer.
Topics: Doxorubicin; Phospholipids; Molecular Dynamics Simulation; Congo Red; Humans; Lipid Bilayers; Drug Carriers; MCF-7 Cells
PubMed: 38893446
DOI: 10.3390/molecules29112567 -
Molecules (Basel, Switzerland) May 2024Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy,...
Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy, but these come with side effects and limitations. Researchers are exploring natural compounds like baicalin and baicalein, derived from the plant, as potential complementary therapies. This study investigated the effects of baicalin and baicalein on the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel, commonly used chemotherapeutic drugs for breast cancer. The analysis included breast cancer cells (MCF-7) and human endothelial cells (HUVEC-ST), to assess potential effects on healthy tissues. We have found that baicalin and baicalein demonstrated cytotoxicity towards both cell lines, with more potent effects observed in baicalein. Both flavonoids, baicalin (167 µmol/L) and baicalein (95 µmol/L), synergistically enhanced the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel in breast cancer cells. In comparison, their effects on endothelial cells were mixed and depended on concentration and time. The results suggest that baicalin and baicalein might be promising complementary agents to improve the efficacy of doxorubicin and docetaxel anticancer activity. However, further research is needed to validate their safety and efficacy in clinical trials.
Topics: Humans; Flavonoids; Flavanones; Docetaxel; Doxorubicin; MCF-7 Cells; Apoptosis; Breast Neoplasms; Female; DNA Damage; Drug Synergism; Antineoplastic Agents; Cell Survival; Human Umbilical Vein Endothelial Cells
PubMed: 38893380
DOI: 10.3390/molecules29112503 -
Molecules (Basel, Switzerland) May 2024Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood-brain...
The Application of Ultrasmall Gold Nanoparticles (2 nm) Functionalized with Doxorubicin in Three-Dimensional Normal and Glioblastoma Organoid Models of the Blood-Brain Barrier.
Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood-brain barrier (BBB). Nanoparticles can be an attractive solution for the treatment of GBM as they can transport drugs across the BBB into the tumor. In this study, normal and GBM organoids comprising six brain cell types were developed and applied to study the uptake, BBB penetration, distribution, and efficacy of fluorescent, ultrasmall gold nanoparticles (AuTio-Dox-AF647s) conjugated with doxorubicin (Dox) and AlexaFluor-647-cadaverine (AF647) by confocal laser scanning microscopy (CLSM), using a mixture of dissolved doxorubicin and fluorescent AF647 molecules as a control. It was shown that the nanoparticles could easily penetrate the BBB and were found in normal and GBM organoids, while the dissolved Dox and AF647 molecules alone were unable to penetrate the BBB. Flow cytometry showed a reduction in glioblastoma cells after treatment with AuTio-Dox nanoparticles, as well as a higher uptake of these nanoparticles by GBM cells in the GBM model compared to astrocytes in the normal cell organoids. In summary, our results show that ultrasmall gold nanoparticles can serve as suitable carriers for the delivery of drugs into organoids to study BBB function.
Topics: Doxorubicin; Glioblastoma; Metal Nanoparticles; Gold; Humans; Blood-Brain Barrier; Organoids; Brain Neoplasms; Cell Line, Tumor
PubMed: 38893345
DOI: 10.3390/molecules29112469 -
International Journal of Molecular... May 2024Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have...
Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups ( > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.
Topics: Animals; Liraglutide; Doxorubicin; Cardiotoxicity; Male; Rats; Rats, Wistar; Oxidative Stress; Myocardium; NF-kappa B; Tumor Necrosis Factor-alpha; Heart
PubMed: 38892020
DOI: 10.3390/ijms25115833 -
International Journal of Molecular... May 2024Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in family members have also been...
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, -deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
Topics: Podocytes; Animals; Mice; Humans; Mice, Knockout; Doxorubicin; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing; Apoptosis; Nephrotic Syndrome; Male; Tumor Suppressor Proteins
PubMed: 38891998
DOI: 10.3390/ijms25115808 -
International Journal of Nanomedicine 2024While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still...
BACKGROUND
While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.
METHODS
We exploited nanoparticle coordination between ferric (Fe) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula's toxicity, imaging, and synergistic therapeutic effects.
RESULTS
The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.
CONCLUSION
Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy.
Topics: Doxorubicin; Animals; Humans; Telomerase; Cell Line, Tumor; Mice; DNA; Tissue Distribution; Nanoparticles; Neoplasms; Ferroptosis; Antibiotics, Antineoplastic; Mice, Inbred BALB C; Drug Carriers
PubMed: 38882546
DOI: 10.2147/IJN.S461774