Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
Humans ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors* ; Drug Resistance, Neoplasm/drug effects* ; ErbB Receptors/genetics* ; Animals ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects* ; Methylation/drug effects* ; Saponins/administration & dosage* ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; Doxorubicin/pharmacology* ; Paclitaxel/pharmacology* ; Female ; Repressor Proteins

Astragali Radix (AR), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use. While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy (DIC); however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action. Through network medicine analysis, astragaloside IV (AsIV) and formononetin (FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsIV-FMT combination (AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsIV and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.
Animals ; Doxorubicin/adverse effects* ; Saponins/administration & dosage* ; Isoflavones/pharmacology* ; Rats ; Cardiomyopathies/prevention & control* ; Mice ; Fatty Acids/metabolism* ; Myocytes, Cardiac/metabolism* ; Triterpenes/administration & dosage* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Cardiotonic Agents/administration & dosage* ; Mice, Inbred C57BL ; Cell Line ; Astragalus Plant/chemistry* ; Astragalus propinquus

OBJECTIVE: Cancer remains a significant global health challenge, necessitating the development of effective treatment approaches. Developing synergistic therapy can provide a highly promising strategy for anti-cancer treatment through combining the benefits of various mechanisms. METHODS: In this study, we developed a synergistic strategy for chemo-photothermal therapy by constructing nanocomposites using gold nanorods (GNRs) and tetrahedral framework nucleic acids (tFNA) loaded with the anti-tumor drug doxorubicin (DOX). RESULTS: Our in vitro studies have systematically clarified the anti-cancer behaviors of tFNA-DOX@GNR nanocomposites, characterized by their enhanced cellular uptake and proficient lysosomal escape capabilities. It was found that the key role of tFNA-DOX@GNR nanocomposites in tumor ablation is primarily due to their capacity to induce cytotoxicity in tumor cells via a photothermal effect, which generates instantaneous high temperatures. This mechanism introduces various responses in tumor cells, facilitated by the thermal effect and the integrated chemotherapeutic action of DOX. These reactions include the induction of endoplasmic reticulum stress, characterized by elevated reactive oxygen species levels, the promotion of apoptotic cell death, and the suppression of tumor cell proliferation. CONCLUSION This work exhibits the potential of synergistic therapy utilizing nanocomposites for cancer treatment and offers a promising avenue for future therapeutic strategies.
Doxorubicin/chemistry* ; Gold/chemistry* ; Nanotubes/chemistry* ; Humans ; Nanocomposites/chemistry* ; Cell Line, Tumor ; Nucleic Acids/chemistry* ; Antibiotics, Antineoplastic/pharmacology* ; Antineoplastic Agents/administration & dosage*

Uterine smooth muscle tumor of uncertain malignant potential (STUMP) is a mesenchymal tumor which lies along the spectrum of smooth muscle neoplasm of the uterus. This type of neoplasm has morphologic features intermediate between the benign leiomyoma and the malignant leiomyosarcoma but is characterized by distinct pathologic findings. STUMPs are rare and standardized treatment for these neoplasms remains to be controversial as its behavior and clinical course is unpredictable and response to various treatments remains to be challenging up to this time. Due to the rarity of these cases, consensus on the standardized treatment on the best surgical approach and adjuvant therapy has not been reached. This study presents a 40-year-old nulligravida who had initial surgical resection of uterine mass but had recurrence of a suprapubic mass with complete treatment of eight cycles of doxorubicin and now presenting with stable disease.

Lymphomas represent one of the most common malignant diseases in young men and an important issue is how treatments will affect their reproductive health. It has been hypothesized that chemotherapies, similarly to environmental chemicals, may alter the spermatogenic epigenome. Here, we report the genomic and epigenomic profiling of the sperm DNA from a 31-year-old Hodgkin lymphoma patient who faced recurrent spontaneous miscarriages in his couple 11-26 months after receiving chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In order to capture the potential deleterious impact of the ABVD treatment on mutational and methylation changes, we compared sperm DNA before and 26 months after chemotherapy with whole-genome sequencing (WGS) and reduced representation bisulfite sequencing (RRBS). The WGS analysis identified 403 variants following ABVD treatment, including 28 linked to genes crucial for embryogenesis. However, none were found in coding regions, indicating no impact of chemotherapy on protein function. The RRBS analysis identified 99 high-quality differentially methylated regions (hqDMRs) for which methylation status changed upon chemotherapy. Those hqDRMs were associated with 87 differentially methylated genes, among which 14 are known to be important or expressed during embryo development. While no variants were detected in coding regions, promoter regions of several genes potentially important for embryo development contained variants or displayed an altered methylated status. These might in turn modify the corresponding gene expression and thus affect their function during key stages of embryogenesis, leading to potential developmental disorders or miscarriages.
Humans ; Male ; Hodgkin Disease/drug therapy* ; Adult ; DNA Methylation/drug effects* ; Bleomycin/therapeutic use* ; Spermatozoa/metabolism* ; Vinblastine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Abortion, Habitual/genetics* ; Doxorubicin/therapeutic use* ; Dacarbazine/therapeutic use* ; Female ; Pregnancy

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

OBJECTIVE: To investigate the mechanism of circular RNA RAD18 (CircRAD18 ) in regulating daunorubicin (DNR) resistance in acute myeloid leukemia (AML) cells through the miR-185-5p/hepatoma-derived growth factor ( HDGF) axis. METHODS: Real-time fluorescence quantitative PCR and immunoblotting were applied to detect the expression of CircRAD18 , miR-185-5p, and HDGF in human AML cell lines HL-60, U937, and human AML drug-resistant cell line KG1a. KG1a cells were cultured in vitro and randomly divided into control group, DNR group, DNR+negative control group, DNR+CircRAD18 knockdown group, and DNR+CircRAD18 knockdown+miR-185-5p inhibitor group. After transfection, real-time fluorescence quantitative PCR and immunoblotting were applied to detect the expression of CircRAD18 , miR-185-5p, and HDGF of cells, CCK-8 method and Ki-67 immunofluorescence staining were applied to detect cell proliferation, flow cytometry was applied to detect cell apoptosis, and immunoblotting was applied to detect the expression of cell proliferation, apoptosis and drug resistance related proteins in each group. The double luciferase reporter gene experiment was applied to detect the targeting regulation of CircRAD18 on miR-185-5p, and miR-185-5p on HDGF in KG1a cells. RESULTS: Compared with HL-60 and U937 cells, the expression of CircRAD18 , and HDGF mRNA and protein in KG1a cells increased (all P <0.05), while miR-185-5p decreased ( P <0.05). Compared with the control group, the CircRAD18 expression, HDGF mRNA and protein expression, cell viability, proliferation rate, and PCNA, Bcl-2, BCRP, and P-gp protein expression in the DNR+CircRAD18 knockdown group decreased (all P <0.05), while miR-185-5p expression, apoptosis rate, and Bax protein expression increased (all P <0.05). There were no obvious changes in all indicators of cells in the DNR group compared with control group ( P >0.05). Compared with the DNR group, the CircRAD18 expression, HDGF mRNA and protein expression, cell viability, proliferation rate, PCNA, Bcl-2, BCRP, and P-gp protein expression in the DNR+CircRAD18 knockdown group decreased (all P < 0.05), while miR-185-5p expression, apoptosis rate, and Bax protein expression increased (all P < 0.05). There were no obvious changes in all indicators of cells in the DNR+negative control group compared with DNR group (P >0.05). Compared with the DNR+CircRAD18 knockdown group, the HDGF mRNA and protein expression, cell viability, proliferation rate, PCNA, Bcl-2, BCRP, and P-gp protein expression in the DNR+CircRAD18 knockdown+miR-185-5p inhibitor group increased (all P < 0.05), while miR-185-5p expression, apoptosis rate, and Bax protein expression decreased (all P < 0.05). CircRAD18 was able to target and down-regulate the expression of miR-185-5p in KG1a cells, and miR-185-5p was able to target and down-regulate the HDGF expression. CONCLUSION Knocking down CircRAD18 can reduce HDGF expression by up-regulating miR-185-5p, thereby weakening DNR resistance in AML cells, inhibiting KG1a cell proliferation under DNR treatment, and promoting apoptosis.
Humans ; MicroRNAs/metabolism* ; Leukemia, Myeloid, Acute ; Daunorubicin/pharmacology* ; Drug Resistance, Neoplasm ; Apoptosis ; RNA, Circular ; Intercellular Signaling Peptides and Proteins/metabolism* ; Cell Proliferation ; HL-60 Cells ; Cell Line, Tumor

OBJECTIVE: To explore the molecular mechanism of Shenmai Injection (SMI) against doxorubicin (DOX) induced cardiomyocyte apoptosis. METHODS: A total of 40 specific pathogen-free (SPF) male Sprague Dawley (SD) male rats were divided into 5 groups based on the random number table, including the control group, the model group, miR-30a agomir group, SMI low-dose (SMI-L) group, and SMI high-dose (SMI-H) group, with 8 rats in each group. Except for the control group, the rats were injected weekly with DOX (2 mg/kg) in the tail vein for 4 weeks to induce myocardial injury, and were given different regimens of continuous intervention for 2 weeks. Cardiac function was detected by echocardiography and myocardial pathological changes were observed by Van Gieson (VG) staining. Myocardial injury serum markers, including creatine kinase (CK), lactate dehydrogenase (LDH), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble ST2 (sST2), and growth differentiation factor-15 (GDF-15) were detected by enzyme linked immunosorbent assay (ELISA). Cardiomyocyte apoptosis was observed by terminal deoxynucleotidyl transferase-mediated biotinylated dUTP triphosphate nick end labeling (TUNEL) and transmission electron microscopy, and the expressions of target proteins and mRNA were detected by Western blot and quantitative real time polymerase chain reaction (qRT-RCR), respectively. RESULTS: The treatment with different doses of SMI reduced rat heart mass index and left ventricular mass index (P<0.05), significantly improved the left ventricular ejection fraction (P<0.05), decreased the levels of serum CK, LDH, cTnT, and NT-proBNP (P<0.05 or P<0.01), reduced the levels of serum sST2 and GDF-15 (P<0.05 or P<0.01), decreased the collagen volume fraction, reduced the expressions of rat myocardial type I and type III collagen (P<0.05 or P<0.01), and effectively alleviated myocardial fibrosis. And the study found that SMI promoted the expression levels of miR-30a and Bcl-2 in myocardium, and down-regulated the expression of Bax, which inhibited the activation of Caspase-3 and Caspase-9 (P<0.05 or P<0.01), and improved myocardial cell apoptosis. CONCLUSIONS SMI can alleviate myocardial injury and apoptosis caused by DOX, and its mechanism possibly by promoting the targeted expression of myocardial Bcl-2 protein through miR-30a.
Animals ; Myocytes, Cardiac/metabolism* ; Apoptosis/drug effects* ; MicroRNAs/genetics* ; Rats, Sprague-Dawley ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Doxorubicin/pharmacology* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; Drug Combinations ; Injections ; Rats

OBJECTIVES: To investigate the effects of dihydroartemisinin (DHA) combined with doxorubicin (DOX) on proliferation and apoptosis of triple-negative breast cancer cells and explore the underlying molecular mechanism. METHODS: MDA-MB-231 cells were treated with 50, 100 or 150 μmol/L DHA, 0.5 μmol/L DOX, or with 50 μmol/L DHA combined with 0.5 μmol/L DOX. The changes in proliferation and survival of the treated cells were examined with MTT assay and colony-forming assay, and cell apoptosis was analyzed with flow cytometry. Western blotting was performed to detect the changes in protein expression levels of PCNA, cleaved PARP, Bcl-2, Bax, STAT3, p-STAT3, HIF-1α and survivin. RESULTS: The IC₅₀ of DHA was 131.37±29.87 μmol/L in MDA-MB-231 cells. The cells with the combined treatment with DHA and DOX showed significant suppression of cell proliferation. Treatment with DHA alone induced apoptosis of MDA-MB-231 cells in a dose-dependent manner, but the combined treatment produced a much stronger apoptosis-inducing effect than both DHA and DOX alone. DHA at 150 μmol/L significantly inhibited clone formation of MDA-MB-231 cells, markedly reduced cellular expression levels of PCNA, p-STAT3, HIF-1α and survivin proteins, and obviously increased the expression level of cleaved PARP protein and the Bax/Bcl-2 ratio, and the combined treatment further reduced the expression level of p-STAT3 protein and increased the Bax/Bcl-2 ratio. CONCLUSIONS DHA combined with DOX produces significantly enhanced effects for inhibiting cell proliferation and inducing apoptosis in MDA-MB-231 cells possibly as result of DHA-mediated negative regulation of the STAT3/HIF-1α pathway.
Humans ; STAT3 Transcription Factor/metabolism* ; Apoptosis/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Doxorubicin/pharmacology* ; Triple Negative Breast Neoplasms/metabolism* ; Cell Line, Tumor ; Artemisinins/pharmacology* ; Female ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Survivin

OBJECTIVES: To develop an E-selectin-targeting nanomedicine delivery system that competitively inhibits E-selectin-neutrophil ligand binding to block neutrophil adhesion to vessels and suppress their recruitment to the lesion sites. METHODS: Doxorubicin hydrochloride (DOX)-loaded liposomes (IEL-Lip/DOX) conjugated with E-selectin-affinity peptide IELLQARC were developed using a post-insertion method. Two formulations [2-1P: Mol(PC): Mol(DPI)=100:1; 2-3P: 100:3] were prepared and their modification density and in vitro release characteristics were determined. Their targeting efficacy was assessed in a cell model of LPS-induced inflammation, a mouse model of acute lung injury (ALI), a rat femoral artery model of physical injury-induced inflammation, and a zebrafish model of local inflammation. RESULTS: The prepared IEL-Lip/DOX 2-1P and 2-3P had peptide modification densities of 4.76 and 7.57 pmoL/cm², respectively. Compared with unmodified liposomes, IEL-Lip/DOX exhibited significantly reduced 48-h cumulative release rates at pH 5.5. In the inflammation cell model, IEL-Lip/DOX showed increased uptake by activated inflammatory endothelial cells, and 2-1P exhibited a higher trans-endothelial ability. In ALI mice, the fluorescence intensity of IEL-Lip/Cy5.5 increased significantly in lung tissues by 53.71% [Z-(2-1P)] and 93.41% [Z-(2-3P)], and 2-1P had an increased distribution by 24.19% in the inflammatory lung tissue compared to normal mouse lung tissue. In rat femoral artery models, 2-1P had greater injured/normal vessel fluorescence intensity contrast. In the zebrafish models, both 2-1P and 2-3P showed increased aggregation at the site of inflammation. CONCLUSIONS This E-selectin-targeting nanomedicine delivery system efficiently targets activated inflammatory endothelial cells to increase drug concentration at the inflammatory site, which sheds light on new strategies for treating neutrophil-mediated inflammatory diseases and practicing the concept of "one drug for multiple diseases".
Animals ; Liposomes ; Rats ; Nanomedicine ; E-Selectin ; Drug Delivery Systems ; Inflammation/drug therapy* ; Mice ; Doxorubicin/analogs & derivatives* ; Zebrafish ; Acute Lung Injury/drug therapy*