Doxorubicin Chemotherapy Research Articles

Multi-drug resistance-1 (MDR-1) gene expression in MCF-7 cells after treated with doxorubicin-deoxyelephantopin combination and prediction of inhibitory activity against Pgp receptors with in silico

Doxorubicin chemotherapy has been a strong focus in breast cancer research. Side effects, toxicity and resistance have been extensively studied. One proposed solution to these issues that its combination with deoxyelephantopin. Deoxyelephantopin is known to be toxic in many cancer cells but safe in normal cells. IC50 of each compound were determined by using a MTT assay, and the MDR-1 gene mRNA expression were determined by using qPCR method, while the interaction of doxorubicin in combination with deoxyelephantonin on Pgp receptor were predicted by using an in silico approach. The IC50 of deoxyelephantopin was found to be 11.2 µg/mL, while IC50 of doxorubicin was 448 nM IC50 values showed a deoxyelephantopin-doxorubicin combination was able to reduce MDR-1 expression by 19% compared to doxorubicin and ½ IC50 values indicated that the combination formula reduced the expression by 15% over doxorubicin alone. The affinity of doxorubicin and deoxyelephantopin is -12.16 kcal/mol and -9.51 kcal/mol, respectively, while the affinity of doxorubicin after combine with deoxyelephantopin decreases from -12,16 kcal/mol to -11,25 kcal/mol due to the release of one Leu 221 hydrogen bond. The combination of doxorubicin with deoxyelephantopin is able to reduce expression and suppress the function of the Pgp protein.

089. TACE for Residive Malignant Peripheral Nerve Sheath Tumor and Leiomyosarcoma: Case Series

Background: Malignant peripheral nerve sheath tumors (MPNST) are malignant, locally aggressive soft tissue sarcomas (STS) of the peripheral nerve or nerve sheath cells. Leiomyosarcomas are malignant tumors originating from the smooth muscle. Transarterial chemoembolization (TACE) is an interventional treatment to deliver chemoembolic materials. Case: First case is a 50-year-old male visited Oncology Surgery Polyclinic due to the presence of a tumor on his left forearm that was progressively increasing in size during the past two months. The MRI was done, the diagnosis of a residive malignant peripheral nerve sheath tumor was made. Second case is a 40-year-old female visited the Oncology Surgery Polyclinic due to the presence of a tumor on her right breast that was progressively increasing in size and the diagnosis of a Leiomyosarcoma at the right breast was made. Transarterial chemoembolization (TACE) was performed to both of the cases. Conclusion: MPNST and Leiomyosarcoma are malignant tumor that can be treated with doxorubicin chemotherapy through the TACE procedure.

Targeted delivery of Saikosaponin A and doxorubicin via hyaluronic acid-modified ZIF-8 nanoparticles for TNBC treatment: Inhibiting metastasis and reducing cardiotoxicity

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, making traditional hormone and targeted therapies ineffective. Chemotherapy remains the primary treatment for TNBC; however, it has failed to adequately address the high rates of recurrence and metastasis, underscoring the urgent need for new therapeutic strategies. This study investigates Saikosaponin A (SSA), a compound extracted from traditional Chinese medicine, for its potential to enhance the efficacy of doxorubicin (DOX) chemotherapy while reducing TNBC metastasis and mitigating DOX-induced cardiotoxicity.We first confirmed SSA's cardioprotective effects against DOX-induced cardiotoxicity, highlighting its potential as an adjunctive therapy for TNBC chemotherapy. Subsequently, through network pharmacology analysis, we identified that SSA may inhibit TNBC progression and metastasis by downregulating integrin β3, a key regulatory factor in tumor development. This was further validated through both in vivo and in vitro experiments. To address the poor bioavailability of SSA, we developed a novel drug delivery system utilizing hyaluronic acid (HA)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles for the co-delivery of SSA and DOX. This nano-drug system exhibited excellent stability and high drug-loading capacity, with loading efficiencies of 40.07 % for SSA and 43.07 % for DOX. After 24 h of nano-drug administration, the DOX concentration in the group using the nano-delivery system was 5.01 times higher than control group, demonstrated enhanced tumor-targeting capability. Furthermore, after 14 days of treatment, the tumor volume was reduced by 80.8 % compared to the control group, indicating significantly improved therapeutic efficacy (all P < 0.05).This study systematically evaluates the potential of this dual drug-loaded nanocarrier in improving TNBC treatment, reducing DOX-induced cardiotoxicity, and inhibiting metastasis, offering a novel therapeutic approach that integrates traditional medicine with advanced nanotechnology.

Hyaluronic acid-functionalized ruthenium photothermal nanoenzyme for enhancing osteosarcoma chemotherapy: Cascade targeting and bidirectional modulation of drug resistance

Insufficient drug delivery efficiency in vivo and robust drug resistance are two major factors to induce suboptimal efficacy in chemotherapy of osteosarcoma (OS). To address these challenges, we developed polysaccharide hyaluronic acid (HA)-functionalized ruthenium nanoaggregates (Ru NAs) to enhance the chemotherapy of doxorubicin (DOX) for OS. These NAs, comprising Ru nanoparticles (NPs) and alendronate-modified HA (HA-ALN), effectively load DOX, resulting in DOX@Ru-HA-ALN NAs. The combination of HA and ALN in NAs ensures outstanding cascade targeting towards tumor-invaded bone tissues and CD44-overexpressing tumor cells, maximizing therapeutic efficacy while minimizing off-target effects. Concurrently, the Ru NPs in NAs function as “smart” photoenzymatic agent to not only in situ relieve hypoxia of OS via the catalysis of overexpressed H2O2 to produce O2, but also generate mild photothermal effect under 808-nm laser irradiation. They can bidirectionally overcome drug resistance of DOX via downregulation of resistance-related factors including multi-drug resistant associate protein, P-glycoprotein, heat shock factor 1, etc. The integration of cascade targeting with bidirectional modulation of drug resistance positions Ru-HA-ALN NAs to substantially enhance DOX chemotherapy for OS. Therefore, the present work highlights the potential of polysaccharide-functionalized nanomaterials in advancing tumor chemotherapy by addressing challenges of both delivery efficiency and drug resistance.

Improved Therapeutic Efficacy of Doxorubicin Chemotherapy With Cannabidiol in 4T1 Mice Breast Cancer Model.

High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects. Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor. Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX. This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone.

Therapeutic Effects of Crocin Nanoparticles Alone or in Combination with Doxorubicin against Hepatocellular Carcinoma In vitro.

Crocin (CRO), the primary antioxidant in saffron, is known for its anticancer properties. However, its effectiveness in topical therapy is limited due to low bioavailability, poor absorption, and low physicochemical stability. This study aimed to prepare crocin nanoparticles (CRO-NPs) to enhance their pharmaceutical efficacy and evaluate the synergistic effects of Cro-NPs with doxorubicin (DOX) chemotherapy on two cell lines: human hepatocellular carcinoma cells (HepG2) and non-cancerous cells (WI38). CRO-NPs were prepared using the emulsion diffusion technique and characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Zeta potential, and Fourier transform infrared spectroscopy (FT-IR). Cell proliferation inhibition was assessed using the MTT assay for DOX, CRO, CRO-NPs, and DOX+CRO-NPs. Apoptosis and cell cycle were evaluated by flow cytometry, and changes in the expression of apoptotic gene (P53) and autophagic genes (ATG5 & LC3) were analyzed using real-time polymerase chain reaction. TEM and SEM revealed that CRO-NPs exhibited a relatively spherical shape with an average size of 9.3 nm, and zeta potential analysis indicated better stability of CRO-NPs compared to native CRO. Significantly higher antitumor effects of CRO-NPs were observed against HepG2 cells (IC50 = 1.1 mg/ml and 0.57 mg/ml) compared to native CRO (IC50 = 6.1 mg/ml and 3.2 mg/ml) after 24 and 48 hours, respectively. Annexin-V assay on HepG2 cells indicated increased apoptotic rates across all treatments, with the highest percentage observed in CRO-NPs, accompanied by cell cycle arrest at the G2/M phase. Furthermore, gene expression analysis showed upregulation of P53, ATG5, and LC3 genes in DOX/CRO-NPs co-treatment compared to individual treatments. In contrast, WI38 cells exhibited greater sensitivity to DOX toxicity but showed no adverse response to CRONPs. Although more in vivo studies in animal models are required to corroborate these results, our findings suggest that CRO-NPs can be a potential new anticancer agent for hepatocellular carcinoma. Moreover, they have a synergistic effect with DOX against HepG2 cells and mitigate the toxicity of DOX on normal WI38 cells.

An Unusual Application of Multifunctional Nanozyme Derived from COF: Augmenting Chemoimmunotherapy while Attenuating Cardiotoxicity

AbstractEnhancing therapeutic efficacy while reducing the adverse effects of drugs is crucial in cancer treatments. In this study, nitrogen‐doped carbon nanospheres are synthesized with variable enzymatic activities through the pyrolysis of a covalent organic framework (COF). These nanospheres show increased peroxidase (POD) and oxidase (OXD) activities in the tumor microenvironment, generating reactive oxygen species (ROS) that help eliminate tumor cells. Under normal conditions, they display catalase (CAT) and superoxide dismutase (SOD) activities, promoting antioxidative protection. Their porous structure and π–π/hydrophobic interactions allow for the loading of the chemotherapeutic agent doxorubicin (DOX). The nanospheres are then enveloped by tumor cell membranes, stabilizing the drug load and enabling targeted drug delivery with pH‐sensitive release. This targeted system induces ferroptosis in tumor cells and activates a strong anti‐tumor immune response, leading to enhanced immunotherapy for breast cancer and reduced tumor metastasis to the lungs. Importantly, the varied enzymatic activities of the nanomedicine system help mitigate the cardiotoxicity of DOX chemotherapy, improving cancer treatment while minimizing side effects. This approach introduces a nano‐enzyme drug system with distinctive activities and innovative preparation, setting a new standard for efficient, low‐toxicity cancer therapy.

Combined Chemo- and Photothermal Therapies of Non-Small Cell Lung Cancer Using Polydopamine/Au Hollow Nanospheres Loaded with Doxorubicin.

The chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity, posing challenges in its application for non-small cell lung cancer (NSCLC). This study aims to explore the efficacy of polydopamine/Au nanoparticles loaded with DOX for chemotherapy and photothermal therapy in NSCLC to achieve enhanced efficacy and reduced toxicity. Hollow polydopamine (HPDA)/Au@DOX was synthesized via polydopamine chemical binding sacrificial template method. Morphology was characterized using transmission electron microscopy, particle size and potential were determined using dynamic light scattering, and photothermal conversion efficiency was assessed using near-infrared (NIR) thermal imaging. Drug loading rate and in vitro drug release were investigated. In vitro, anti-tumor experiments were conducted using CCK-8 assay, flow cytometry, and live/dead cell staining to evaluate the cytotoxicity of HPDA/Au@DOX on A549 cells. Uptake of HPDA/Au@DOX by A549 cells was detected using the intrinsic fluorescence of DOX. The in vivo anti-metastasis and anti-tumor effects of HPDA/Au@DOX were explored in mouse lung metastasis and subcutaneous tumor models, respectively. HPDA/Au@DOX with a particle size of (164.26±3.25) nm, a drug loading rate of 36.31%, and an encapsulation efficiency of 90.78% was successfully prepared. Under 808 nm laser irradiation, HPDA/Au@DOX accelerated DOX release and enhanced uptake by A549 cells. In vitro photothermal performance assessment showed excellent photothermal conversion capability and stability of HPDA/Au@DOX under NIR laser irradiation. Both in vitro and in vivo experiments demonstrated that the photothermal-chemotherapy combination group (HPDA/Au@DOX+NIR) exhibited stronger anti-metastatic and anti-tumor activities compared to the monotherapy group (DOX). HPDA/Au@DOX nanosystem demonstrated excellent photothermal effect, inhibiting the growth and metastasis of A549 cells. This nanosystem achieves the combined effect of chemotherapy and photothermal, making it promising for NSCLC treatment.

Changes in Mitochondrial Function and Cell Death Patterns in Peripheral Blood Mononuclear Cells during Trastuzumab Treatment Following Doxorubicin Chemotherapy.

Trastuzumab, a monoclonal antibody which works against human epidermal growth factor receptor 2 (HER2), possibly causes cardiotoxicity through mitochondrial dysfunction. The usefulness of isolated peripheral blood mononuclear cells (PBMCs) in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. This study aimed to determine the temporal changes in mitochondrial function, oxidative stress, and cell death in the isolated PBMCs of HER2-positive breast cancer patients during breast cancer treatment and to compare the changes with HER2-negative breast cancer patients who did not receive trastuzumab therapy. Eighteen newly diagnosed HER2-positive breast cancer women who received sequential doxorubicin and trastuzumab were consecutively recruited. Age- and gender-matched controls with HER2-negative breast cancer were selected. Echocardiography was carried out, and blood samples for the study of cardiac biomarkers and PBMCs were collected periodically during treatment. Only one patient in our cohort developed asymptomatic left ventricular dysfunction during trastuzumab treatment. However, trastuzumab following doxorubicin aggravated subclinical cardiac injury, determined by cardiac troponin and echocardiography. Cellular and mitochondrial oxidative stress in isolated PBMCs remained unchanged throughout breast cancer treatment. Regarding mitochondrial respiration, the maximal respiration and spare respiration capacity was significantly increased in controls after doxorubicin treatment but not in patients who received trastuzumab therapy. Moreover, the percentage of apoptosis and necroptosis in isolated PBMCs was dramatically decreased in the control, compared to patients with trastuzumab treatment. In conclusion, trastuzumab caused subtle myocardial injury and impaired mitochondrial respiration and cell viability in isolated PBMCs.

The protective effect of hydroalcoholic Citrus aurantifolia peel extract against doxorubicin-induced nephrotoxicity

Background and purpose: Doxorubicin chemotherapy is a widely used treatment for various cancers, including breast, ovarian, and uterine cancers, among others. However, long-term use can cause nephrotoxicity side effects. Some citrus flavonoids have demonstrated nephroprotective activity; therefore, this study aimed to test the nephroprotective effectiveness of Citrus aurantifolia peel extract in protecting and reducing kidney damage caused by doxorubicin. Experimental approach: Citrus aurantifolia peel was dried, ground, and extracted by ultrasonication (70% ethanol), then the extract was dried. Twenty-five female Sprague-Dawley rats were divided into 5 groups including the normal group (control), positive control (doxorubicin) group receiving doxorubicin at the repeated intraperitoneal (i.p.) dose of 4 mg/kg/day on days 2, 6, 10, and 14, and treatment groups receiving Citrus aurantifolia peel extract (CPE) with the doses of 100, 200, and 400 mg/kg/day orally for 14 days, and doxorubicin (4 mg/kg/day, i.p.) on days 2, 6, 10 and 14. On day 15, the rats were euthanized for the measurements of MDA, superoxide dismutase (SOD), catalase, kidney function (measuring blood urea nitrogen (BUN), creatinine, albumin serum levels), and renal histopathology. Findings/Results: The CPE yield was 16.13%. CPE could significantly reduce the levels of MDA, and increase SOD and catalase activities compared with the doxorubicin-induced nephrotoxic model. CPE could increase renal function by reducing BUN and creatinine levels, increasing albumin, and improving the histopathology of the kidney. Conclusion and implications: CPE has a potential effect as nephroprotective against doxorubicin-induced toxicity in renal through antioxidant capacities and increased renal function.

Divergent Immediate and Delayed Effects of Juvenile Exposure to Doxorubicin on the Thymus in C57BL/6 Mice.

The understanding of alterations within the immune system following doxorubicin (DOX) chemotherapy, and subsequent restoration, in childhood cancer survivors remains limited. This investigation endeavors to elucidate the immediate and delayed changes in thymic immune cell populations and their phenotypes in response to clinically relevant low doses of DOX in a juvenile mouse model. Male mice underwent a regimen of repeated low-dose DOX intraperitoneal injections at 4 mg/kg/week for three consecutive weeks. One week after the last dose of DOX, a subset of mice was euthanized to assess the immediate effects of DOX administration. A second subset of mice was euthanized five weeks after the last DOX dose to evaluate the delayed effects. Thymic samples were collected for multiparameter flow cytometry analysis to evaluate alterations in immune cell composition and phenotype. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure gene expression of- cytokines and senescence markers. One week following DOX administration, DOX treatment resulted in significant decline in thymus weight, with notable alterations in immune cell subpopulations. Reduced frequencies of mature CD3+CD4+ and CD3+CD8+ T cells were observed, along with changes in proliferation and exhaustion markers. Gene expression analysis revealed upregulation of Foxn, Pax1, Ifnγ, and Il7 alongside decreased Il6 and Il17 expression. Furthermore, Cdkn1a (p21Cip1) expression was elevated, suggesting immunosenescence. Five weeks following DOX administration, delayed effects of DOX treatment manifested in rebound increase in thymus weight and altered frequencies of CD4+ and CD8+ T cell subsets, with distinct patterns of proliferation and exhaustion observed. Notably, central memory CD4+ T cells exhibited significant decrease in frequency, while naive and effector memory CD4+ T cells showed reduced proliferation (Ki67+) and PD1 expression. Similar trends were observed in CD8+ T cell subsets, indicating selective effects of DOX on T cell differentiation and function. Although expression of thymus-related genes was normalized, p21Cip1 gene expression remained elevated. DOX treatment elicits a multifaceted influence on immune cell subsets and thymic weight. Immediate effects included thymic atrophy and reductions in mature T cell populations, while delayed effects showed rebound thymic hyperplasia and selective changes in CD4+ and CD8+ T cell subsets. Notably, both central memory and effector memory T cells exhibited reduced proliferation and exhaustion, suggesting unique impacts of DOX on immune cell function. The enduring elevation in p21Cip1 gene expression 5 weeks after DOX treatment suggests an immunosenescent phenotype. These observations collectively illuminate the formidable task of preserving immune competence and overall well-being in childhood cancer survivors subjected to DOX therapy.

Evaluation of oral mucositis level and affecting factors in cancer patients receiving chemotherapy.

This study aimed to evaluate the severity of oral mucositis and the contributing factors among cancer patients undergoing chemotherapy. This study was planned cross-sectional. The study was conducted at a medical oncology clinic between January and July 2022. The sample consisted of 245 patients with cancer receiving chemotherapy. Data were collected using a personal, oral health and disease-related characteristics questionnaire and the World Health Organization Oral Mucositis Assessment Scale by researchers. Intraoral examination of the patients was carried out by researchers. The data were analyzed by independent-sample t-tests, Chi-square tests, paired-sample t-tests, and multivariate logistic regression (p < 0,05). The patients had mean age 62.31 ± 10.70. Patients of 32.7% were with lung cancer. 52%of the patients (n = 128) receiving chemotherapy developed oral mucositis. The independent variables the presence chronic disease(OR:1.85), chemotherapy protocol (OR:3.52) and the dependent variables ECOG performance score (OR:2.25) were variable that affected the development of oral mucositis (p < 0.05). Patients of 35.5% were oral mucositis score of 1. Patients those who had breast cancer, who received doxorubicin or cyclophosphamide chemotherapy protocols, and who had previously developed oral mucositis were found to have a higher rate of oral mucositis (p < 0.05). In addition, oral mucositis was more prevalent in patients with chronic diseases other than cancer (57%), those who used medication continuously (57.2%), those with oral and dental diseases (56.9%), those who had dental check-ups before cancer treatment (79.2%), and those who had information about oral mucositis(70.2%) (p < 0.05). In conclusion, nearly half of the patients (52%, n = 128) receiving chemotherapy developed oral mucositis and of all patients of 35.5% had an oral mucositis score of 1 in the second round of chemotherapy. Patients those who had breast cancer, who received doxorubicin or cyclophosphamide chemotherapy protocols, and who had previously developed oral mucositis were found to have a higher rate of oral mucositis.

Surface engineering of metal-organic framework nanoparticles-based miRNA carrier: Boosting RNA stability, intracellular delivery and synergistic therapy

MicroRNAs (miRNAs) are small noncoding RNAs that are critical for the regulation of multiple physiological and pathological processes, thus holding great clinical potential. However, the therapeutic applications of miRNAs are severely limited by their biological instability and poor intracellular delivery. Herein, we describe a dual-layers surface engineering strategy to design an efficient miRNA delivery nanosystem based on metal–organic frameworks (MOFs) incorporating lipid coating. The resulting nanoparticle system was demonstrated to protect miRNA from ribonuclease degradation, enhance cellular uptake and facilitate lysosomal escape. These ensured effective miRNA mediated gene therapy, which synergized with MOF-specific photodynamic therapy and pre-encapsulated doxorubicin (Dox) chemotherapy to provide a multifunctional with therapeutic effectiveness against cencer cells The mechanisms of miRNA binding and Dox loading were revealed, demonstrating the potential of the present MOFs surface-engineered strategy to overcome their inherent pore-size restriction for macromolecular miRNA carrying, enableefficient co-delivery. In vitro studies revealed the potential of our multifunctional system for miRNA delivery and the demonstrated the therapeutic effectiveness against cancer cells, thereby providing a versatile all-in-one MOFs strategy for delivery of nucleic acids and diverse therapeutic molecules in synergistic therapy.

The interplay between doxorubicin chemotherapy, antioxidant system, and cardiotoxicity: Unrevealing of the protective potential of tannic acid.

Cardiotoxicity is the leading side effect of anthracycline-based chemotherapy. Therefore, it has gained importance to reveal chemotherapy-supporting strategies and reliable agents with their mechanisms of action. Tannic acid (TA), a naturally occurring plant polyphenol, has diverse physiological effects, including anti-inflammatory, anticarcinogenic, antioxidant, and radical scavenging properties. Therefore, this study was designed to investigate whether TA exerts a protective effect on mechanisms contributing to anthracycline-induced cardiotoxicity in rat heart tissues exposed to doxorubicin (DOX). Rats were randomly divided into control and experimental groups and treated with (18mg/kg) DOX, TA (50mg/kg), and DOX+TA during the 2 weeks. Cardiac gene markers and mitochondrial DNA (mtDNA) content were evaluated in the heart tissues of all animals. In addition to major metabolites, mRNA expression changes and biological activity responses of components of antioxidant metabolism were examined in the heart tissues of all animals. The expression of cardiac gene markers increased by DOX exposure was significantly reduced by TA treatment, whereas mtDNA content, which was decreased by DOX exposure, was significantly increased. TA also improved antioxidant metabolism members' gene expression and enzymatic activity, including glutathione peroxidase, glutathione s-transferase, superoxide dismutase, catalase, and thioredoxin reductase. This study provides a detailed overview of the current understanding of DOX-induced cardiotoxicity and preventive or curative measures involving TA.

Abstract Mo011: Selective silencing of p38δ is cardioprotective in female mice during doxorubicin chemotherapy

Introduction: Dose-dependent cardiotoxicity limits the efficacy of chemotherapeutic agent doxorubicin (DOX). p38δ is one of four p38 mitogen-activated protein kinase isoforms that regulate DOX-induced cardiotoxicity (DIC). p38δ genetic deletion protects female mice from DIC. In the absence of selective pharmacologic inhibitors of p38δ, docosanoic acid (DCA) conjugate-mediated delivery of chemically engineered small interfering RNA (siRNA) provides a novel avenue to achieve selective, efficient, durable, and nontoxic in vivo p38δ silencing in the heart. Hypothesis: The selective silencing of p38δ is cardioprotective from DIC in female mice. Methods: Following the screening of a panel of p38δ-selective siRNA sequences, the lead siRNA si-p38δ-1, with the highest silencing efficacy and potency in vitro, was identified. 15-week-old female mice were subcutaneously injected with 20 mg/kg of DCA-conjugated chemically stabilized si-p38δ-1 (n = 3) or the non-targeting control (NTC) siRNA (n = 3) twice 10 hours apart. p38δ silencing in mouse hearts was measured 14 days later by assessing mRNA and protein expression. To evaluate the effect of p38δ silencing after acute DOX treatment, the mice were administered si-p38δ-1 (n = 5) or NTC (n = 5), followed by DOX treatment (30 mg/kg) six days later. The study concluded 11 days after DOX treatment. Morbidity was assessed by assigning health scores daily. Electrocardiography, echocardiography, and optical mapping were performed to evaluate cardiac function. Results: si-p38δ-1 led to 80% silencing of p38δ in mouse hearts 14 days after administration, without any cardiotoxic effects. si-p38δ-1-treated female mice exhibited diminished DOX-induced morbidity (p = 0.003) and were protected from developing calcium alternans (CAs) 11 days post-DOX treatment, compared to NTC-treated counterparts. Thus, DOX-induced CAs, indicative of calcium mishandling, were observed in 75% (3/4) NTC-treated mice and 0% (0/5) si-p38δ-1-treated mice. Conclusion: Efficient and well-tolerated in vivo p38δ silencing by si-p38δ-1 in mouse hearts mitigated DOX-induced morbidity and calcium mishandling in female mice, highlighting the therapeutic potential of p38δ silencing for alleviating DIC in female cancer patients.

Abstract Mo022: Doxorubicin induces cardiomyopathy through Wnt5a-mediated induction of senescence

Doxorubicin (DOX) is a chemotherapeutic agent used to treat cancer, but its clinical use is restricted due to cardiotoxicity. Senescence is defined by resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Elimination of senescent cells can improve cardiac dysfunction, suggesting that senescent cardiomyocytes (CMs) contribute to impaired heart function. Although DOX induces senescence in CMs, little is known about the mechanisms mediating DOX-induced senescence and cardiomyopathy. Wnt5a, a non-canonical Wnt ligand, is an important player in cardiac diseases and is upregulated in induced pluripotent stem cell (iPSC)-derived CMs from patients with heart failure induced by DOX chemotherapy. However, the role of Wnt5a in mediating DOX-induced cardiomyopathy remains elusive. Wnt5a protein expression was increased (4.4-fold, p&lt;0.001) in mouse hearts with DOX-induced cardiomyopathy. Upregulation of Wnt5a following DOX treatment was also observed in neonatal rat CMs (NRCMs), and the degree of upregulation was more prominent in CMs (2.1-fold) than in non-CMs (1.1-fold). In NRCMs, Wnt5a induced senescent phenotypes, including increases in the p16 protein level, the number of γH2AX foci per cell and SA-β-gal activity. Wnt5a knockdown reduced DOX-induced increases in the p16 protein level in NRCMs, suggesting that Wnt5a mediates DOX-induced CM senescence. To assess the role of endogenous CM Wnt5a in mediating DOX-induced cardiomyopathy, we generated Myh6 -cre Wnt5a fl/fl ( Wnt5a cKO ) mice, in which Wnt5a is knocked out in a CM-specific manner. DOX-treated Wnt5a cKO mice showed little difference in ejection fraction (EF) compared to PBS-treated Wnt5a cKO mice (56.64 ± 6.17% and 57.60 ± 5.23%), while DOX-treated Wnt5a fl/fl mice showed a significant decrease in EF (34.63 ± 3.65%, p&lt;0.0001). These results suggest that Wnt5a deletion in CMs impedes the progression of DOX-induced cardiac dysfunction, positioning Wnt5a as a novel therapeutic target for the prevention of DOX-induced cardiomyopathy.

Effect of Coenzym Q10 on Doxorubicin-induced Cardiotoxicity in Non Hodgkin's Lymphoma Patients

BACKGROUND : Non-Hodgkin's Lymphoma is a primary malignancy in the Lymph Nodes and lymphoid tissue originating from B lymphocytes, T lymphocytes and Natural Killer (NK) cells. Therapy for Non-Hodgkin's Lymphoma chemotherapy can be given alone or combined with radioactive therapy. Doxorubicin is a chemotherapy drug used for lymphoma with side effects, one of which is cardiotoxic effects. AIMS : To prove that coenzyme Q10 can reduce the cardiotoxic effect of doxorubicin chemotherapy in non-Hodgkin's lymphoma patients METHOD : Intervention study with a randomized pre and post test double blind control group design with 34 NHL patients undergoing chemotherapy. The treatment group received additional therapy with coenzyme Q10 300mg/day for 12 weeks while the controls received placebo. The cardiotoxic effects examined were assessed based on the results of Electrocardiography and Echocardiography. RESULT : The treatment group with coenzyme Q10 supplementation after the 4th chemotherapy showed a decrease in echocardiography results in 3 patients (18%) and in the control group 17 patients (100%). There was a significant difference in the echocardiography results of the treatment and control groups (p=0.001). There were no drug side effects in both groups CONCLUSION : Coenzyme Q10 supplementation provides an improvement in the cardiotoxic effects of doxorubicin in non-Hodgkin's lymphoma patients, on echocardiography, but not on Electrocardiography.

A Multicenter, Single-Arm, Prospective Trial to Evaluate Efficacy and Safety of Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Carboplatin (DD-MVACarbo) Chemotherapy for Cisplatin-Ineligible Patients with Advanced Urothelial Cancer: Study Protocol of the CARBUNCLE Trial.

Unresectable, metastatic, advanced urothelial carcinoma (aUC) is an aggressive disease and is treated with platinum-containing first-line chemotherapy, followed by immune checkpoint inhibitors and antibody-drug conjugates. Response to first-line chemotherapy is a vital priority in sequential treatment strategies because a better response to first-line chemotherapy is associated with a better response to subsequent therapies. Gemcitabine plus carboplatin chemotherapy is conventionally recommended for cisplatin-ineligible patients. This multicenter, single-arm prospective trial will investigate whether dose-dense methotrexate, vinblastine, doxorubicin, and carboplatin (DD-MVACarbo) chemotherapy is superior to gemcitabine plus carboplatin chemotherapy in terms of efficacy in platinum-naïve, cisplatin-ineligible patients with aUC. After screening and registration, a total of 46 patients will be treated with this novel chemotherapy regimen. The primary endpoint is the objective response rate. The secondary endpoints include disease control rate, patient-reported outcomes, and adverse events. No evidence of this novel intervention is available as of July 2024. The results are expected to change the standard of care and improve the management of patients with aUC.

Molecular genetic indicators of the probability of early myocardial systolic dysfunction signs in doxorubicin chemotherapy in patients with breast cancer of moderate and low HFA-ICOS risk groups

Aim. To study the association of rs2232228 (HAS3 gene), rs2229774 (RARG gene), rs1056892 (CBR3 gene), rs1786814 (CELF4 gene), rs1695 (GSTP1 gene), rs8187710 (ABCC2 gene), rs7853758 (SLC28A3 gene), rs243865 (MMP­2 gene), rs243866 (MMP­2 gene), rs35068180 (MMP­3 gene), rs522616 (MMP­3 gene), rs679620 (MMP­3 gene), rs17576 (MMP­9 gene), rs3918242 (MMP­9 gene) with the probability of early doxorubicin cardiotoxicity signs in patients with breast cancer of moderate and low HFA-ICOS risk groups.Material and methods. The study included 100 patients (women, over 18 years old) diagnosed with breast cancer who received chemotherapy using doxorubicin.To identify early cardiotoxicity signs, echocardiography was performed before, immediately after and 12 months after the end of chemotherapy. The status of polymorphic variants of the studied genes was determined by real-time polymerase chain reaction.Results. Based on the decrease in global longitudinal myocardial strain (&gt;12%) immediately after and 12 months after the end of chemotherapy, the patients were divided into two following groups: A — early signs of myocardial dysfunction can be diagnosed after the end of chemotherapy (19%); B — early signs of myocardial dysfunction are detected for the first time only 12 months after the chemotherapy end (17%). In patients from category A, a number of allelic variants and genotypes with potential as independent factors for predicting the early signs of myocardial dysfunction were identified, with an emphasis on targets involved in metabolism and detoxification of doxorubicin and its derivatives. In category B, the greatest differences in the frequencies of allelic variants and genotypes were found among target genes encoding matrix metalloproteinases involved in the processes of response to the intensification of oxidative stress caused by doxorubicin and its derivatives.Conclusion. In total, patients in the low- and moderate-risk groups can be divided into at least 2 categories based on molecular genetic testing. For these categories, the development of early signs of doxorubicin-related myocardial dysfunction before the start of chemotherapy can be predicted.

Bicalutamide Enhances Conventional Chemotherapy in In Vitro and In Vivo Assays Using Human and Canine Inflammatory Mammary Cancer Cell Lines.

Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are highly aggressive neoplastic diseases that share numerous characteristics. In IBC and IMC, chemotherapy produces a limited pathological response and anti-androgen therapies have been of interest for breast cancer treatment. Therefore, the aim was to evaluate the effect of a therapy based on bicalutamide, a non-steroidal anti-androgen, with doxorubicin and docetaxel chemotherapy on cell proliferation, migration, tumor growth, and steroid-hormone secretion. An IMC-TN cell line, IPC-366, and an IBC-TN cell line, SUM149, were used. In vitro assays revealed that SUM149 exhibited greater sensitivity, reducing cell viability and migration with all tested drugs. In contrast, IPC-366 exhibited only significant in vitro reductions with docetaxel as a single agent or in different combinations. Decreased estrogen levels reduced in vitro tumor growth in both IMC and IBC. Curiously, doxorubicin resulted in low efficacy, especially in IMC. In addition, all drugs reduced the tumor volume in IBC and IMC by increasing intratumoral testosterone (T) levels, which have been related with reduced tumor progression. In conclusion, the addition of bicalutamide to doxorubicin and docetaxel combinations may represent a potential treatment for IMC and IBC.