Anti-breast Cancer Drug Research Articles

A (Comprehensive) Review of the Application of Quantitative Structure–Activity Relationships (QSARs) in the Prediction of New Compounds with Anti-Breast Cancer Activity

Computational approaches applied in drug discovery have advanced significantly over the past few decades. These techniques are commonly grouped under the term “computer-aided drug design” (CADD) and are now considered one of the key pillars of pharmaceutical discovery pipelines in both academic and industrial settings. In this work, we review Quantitative Structure–Activity Relationships (QSARs), one of the most used ligand-based drug design (LBDD) methods, with a focus on its application in the discovery and development of anti-breast cancer drugs. Critical steps in the QSAR methodology, essential for its correct application—but often overlooked, leading to insignificant or misleading models—are examined. Additionally, current anti-breast cancer treatment strategies were briefly overviewed, along with some targets for future treatments. The review covers QSAR studies from the past five years and includes a discussion of notable works that could serve as models for future applications of this interdisciplinary and complex method and that may help in feature drug design and development.

Bilosomal Co-Encapsulated Tamoxifen and Propranolol for Potentiated Anti-Breast Cancer Efficacy: In Vitro and In Vivo Investigation.

Background/Objectives: Tamoxifen (TAM) is an anti-breast cancer drug suffering from acquired resistance development, prompting cancer relapse. Propranolol (PRO)'s repurposing for cancer therapy has gained interest. This work aimed to investigate combined TAM/PRO therapy for potentiating the anti-breast cancer activity of TAM. The work probed bilosomes versus standard noisome for simultaneous oral and intratumor delivery of TAM and PRO. Methods: Bilosomes comprising Span60, cholesterol, and increasing concentrations of bile salts were prepared together with bile salts containing free standard niosomes. The vesicular size and morphology were characterized. The entrapment and release efficiencies of TAM and PRO from the tailored vesicles were determined. The in vivo investigations of anti-tumor activity of TAM with or without PRO employed the solid Ehrlich carcinoma model. Results: The vesicles of all fabricated dispersions were spherical and negatively charged, with a size ranging from 104 to 182 nm. The entrapment efficiency depended on the nature of the drug, recording values ranging from 87.5% to 97.8% for TAM and from 31.0% to 46.8% for PRO. Incorporation of bile salts into vesicles increased TAM and PRO release compared to standard niosomes. Oral administration of combined TAM/PRO bilosomes showed a significant reduction in tumor growth volume compared to that recorded following naked drug administration. Histopathological investigations reflected a significant decline in tumor giant cells and mitotic figures, implying the in vivo capability of the TAM/PRO combination to interfere with cancer cell proliferation and persistence. Conclusions: The overall results demonstrated the impact of repurposed PRO to enhance the anti-breast cancer activity of TAM when both were co-encapsulated into bilosomes.

Targeting the ERK1/2 and p38 MAPK pathways attenuates Golgi tethering factor golgin-97 depletion-induced cancer progression in breast cancer

BackgroundThe Golgi apparatus is widely considered a secretory center and a hub for different signaling pathways. Abnormalities in Golgi dynamics can perturb the tumor microenvironment and influence cell migration. Therefore, unraveling the regulatory network of the Golgi and searching for pharmacological targets would facilitate the development of novel anticancer therapies. Previously, we reported an unconventional role for the Golgi tethering factor golgin-97 in inhibiting breast cell motility, and its downregulation was associated with poor patient prognosis. However, the specific role and regulatory mechanism of golgin-97 in cancer progression in vivo remain unclear.MethodsWe integrated genetic knockout (KO) of golgin-97, animal models (zebrafish and xenograft mice), multi-omics analysis (next-generation sequencing and proteomics), bioinformatics analysis, and kinase inhibitor treatment to evaluate the effects of golgin-97 KO in triple-negative breast cancer cells. Gene knockdown and kinase inhibitor treatment followed by qRT‒PCR, Western blotting, cell viability, migration, and cytotoxicity assays were performed to elucidate the mechanisms of golgin-97 KO-mediated cancer invasion. A xenograft mouse model was used to investigate cancer progression and drug therapy.ResultsWe demonstrated that golgin-97 KO promoted breast cell metastasis in zebrafish and xenograft mouse models. Multi-omics analysis revealed that the Wnt signaling pathway, MAPK kinase cascades, and inflammatory cytokines are involved in golgin-97 KO-induced breast cancer progression. Targeting the ERK1/2 and p38 MAPK pathways effectively attenuated golgin-97-induced cancer cell migration, reduced the expression of inflammatory mediators, and enhanced the chemotherapeutic effect of paclitaxel in vitro and in vivo. Specifically, compared with the paclitaxel regimen, the combination of ERK1/2 and p38 MAPK inhibitors significantly prevented lung metastasis and lung injury. We further demonstrated that hypoxia is a physiological condition that reduces golgin-97 expression in cancer, revealing a novel and potential feedback loop between ERK/MAPK signaling and golgin-97.ConclusionOur results collectively support a novel regulatory role of golgin-97 in ERK/MAPK signaling and the tumor microenvironment, possibly providing new insights for anti-breast cancer drug development.

Targeting breast cancer resistance protein (BCRP/ABCG2) in cancer.

Breast cancer is one of the most common cancers among women. Nowadays postoperative adjuvant chemotherapy is the mainstay for clinical treatment of breast cancer. However, the emergence of multidrug resistance (MDR) in breast cancer has become a main reason for the failure of clinical chemotherapy. Multiple studies have demonstrated that the formation of MDR in breast cancer is combined with ATP-binding transporters, which are the proteins that can lead to the drug resistance by pumping out chemotherapeutic drugs to reduce their intracellular accumulation. This kind of protein mainly includes P-glycoprotein (Pgp, ABCB1, MDR1), multidrug resistance-associated protein (MRP-1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). The former two transporters have been investigated deeply and widely, while the molecular mechanism of BCRP regulation of breast cancer drug resistance has relatively not much been explored in the area of breast cancer. How to design a novel, effective and non-toxic BCRP inhibitor to reverse the MDR of breast cancer, and boost the success rate of chemotherapy is a serious challenge at present. A detailed overview of the molecular role of BCRP-mediated breast cancer MDR and its inhibitors reported in recent years is provided in this article. The expectation is to provide ideas for clinically addressing MDR in breast cancer, and further guide the direction for the development of new anti-breast cancer drugs and reversal of breast cancer MDR drugs.

Synthesis and Evaluation of 3,5-Disubstituted-1,2,4-Oxadiazolyl Benzamides as Potential Anti-Breast Cancer Agents: In Vitro and In Silico Studies.

Herein, the synthesis, anti-cancer evaluation, and in silico studies of a series of 1,2,4-oxadiazole compounds (8-15) are disclosed. The synthesized molecules were tested in vitro for anti-cancer activity against MCF-7, MDA-MB-231, HeLa, Ishikawa cell lines and human embryonic kidney (HEK-293) cell lines. Among the synthesized compounds, 9 and 15 exhibited significant cytotoxicity, with IC50 values of 7.82 μM and 6.02 μM, respectively, against MCF-7 cell line, better than that of anti-breast cancer drug, tamoxifen (IC50=11.92 μM), used as control. Significantly, both 9 and 15 exhibited very low toxicity (IC50>20 μM) against normal HEK-293 cells. This suggests them as potentially effective anti-cancer lead molecules. The in vitro anti-cancer data was supported by in silico studies which also identified compounds 9 and 15 as potent inhibitors of the 17β-hydroxysteroid dehydrogenase1 (17β-HSD1) proteins, demonstrating strong interactions and stability The atom-based QSAR model exhibited high accuracy, significant regression, and predictive reliability, aiding in understanding and optimizing biological activity. The drug-likeness study of compounds 9 and 15 indicated favorable pharmacokinetics, with in silico toxicity predictions showing compound 15 to be non-toxic. These findings suggest compounds 9 and 15 as potential lead molecules against breast cancer.

A novel approach to breast cancer Assessing the promise of RF16662 on MCF-7 breast cancer cells

Abstract. Breast cancer, a prevalent global health issue, often poses challenges due to resistance apoptosis. This study explores the potential of RF16662, a derivative of naphthyridine, as a novel compound for breast cancer treatment. Naphthyridine compounds, known for inducing necroptosis in cancer cells, offer a unique avenue for addressing apoptosis-resistant cancers. RF16662s efficacy was evaluated through three experiments on MCF-7 breast cancer cells. The MTT cell viability assay demonstrated a strong negative correlation between RF16662 concentration and cell viability, indicating its effectiveness in inhibiting MCF-7 cellular activity. DNA fragmentation analysis revealed substantial DNA fragmentation in cells treated with RF16662, suggesting necroptosis induction. MLKL immunofluorescence confirmed the significant difference in relative MLKL expression between untreated and treated cells, further supporting the induction of necroptosis. This study provides robust evidence of RF16662s efficacy against MCF-7 breast cancer cells. However, variations in MLKL immunofluorescence data suggest the need for repeated experiments to minimize the standard deviation. The results highlight RF16662s potential as an anti-breast cancer drug, offering a promising avenue for future research and potential therapeutic development. While its efficacy against other cancer types remains unknown, RF16662 emerges as a noteworthy candidate in the ongoing quest for innovative breast cancer treatments.

Strategies to Improved Breast Cancer Treatment Associated With Cardiotoxicity

Abstract. In recent years, breast cancer has developed rapidly. Many women suffer from breast cancer, making the study of its treatment extremely important. The drugs used in breast cancer therapy have shown beneficial effects, but some cause cardiotoxic side effects wich deserve close attention. Cardiotoxicity includes a range of effects, such as arrythmia, cardiac dyfunction and even heart failure, which could be a threaten to life health. Therefore, it is crucial and necessary to deal with the cardiotixicity side effect during breast cancer therapy. Doing so will provide patients better options for their treatment. Three drugs have been proven to have cardiotoxic effects, including anthracyclines(eg:Doxorubicin), HER-2-targeting drug(Tratzutmab), and Cyclophosphamide. Although numerous studies have extensively researched how to mitigate the cardiotoxic effects of anti-breast cancer drugs, few articles have summarized and discussed these findings. This current situation results in a lack of comprehensive treatment plans in clinical practice. Therefore, this paper aims to review these studies and discuss the main drugs used to reduce the toxicity of three commonly used antineoplastic agents, in the hope of providing more comprehensive guidance for clinical medication.

Insight into the molecular mechanism of anti-breast cancer therapeutic potential of substituted salicylidene-based compounds using cell-based assays and molecular docking studies

Targeting oxidative stress and inflammatory signaling pathways is an effective cancer prevention and therapy approach. The mechanism of action of synthesized salicylidene-based compounds was investigated in regulating key molecular targets of breast cancer development. Compounds (1), (4), (5), and (7) were found to be more cytotoxic to MCF-7 and 4T1 cells compared to non-cancerous Chang liver cells, while these compounds were cytotoxic to MDA-MB-231 cells, but with poor selectivity. The colony formation assay indicated that bioactive compounds induced significant damage to breast cancer cells, as observed by a reduction in the number of colonies compared to control cells. By inducing a concentration and time-dependent increase of luminescence and fluorescence of phosphatidylserine, and activating the expression of caspases-3, -7, -8, -9 in breast cancer cells, (1) and (7) have shown to induce caspase-dependent apoptosis. The downregulation of NF-kB-p65 and an upregulation of TP53 expression after exposure to bioactive compounds, demonstrated the suppression of two key targets of breast cancer development. Molecular docking studies revealed that selected protein targets strongly interact with bioactive compounds, and the estimated inhibition constants (Ki) of JAK2, STAT3, COX-2, HPV31 E6, EGFR1, TP53, and PARP1 were significantly decreased compared to acetylsalicylic acid. This could be a clear indication that these protein targets are implicated with antiproliferative efficacy, thereby warranting the potential of (1) and (7) to be used as anti-breast cancer drug candidates.

Oleanolic acid purified from the stem bark of Olax subscorpioidea Oliv. inhibits the function and catalysis of human 17β-hydroxysteroid dehydrogenase 1

Cancer is a leading cause of global death. Medicinal plants have gained increasing attention in cancer drug discovery. In this study, the stem bark extract of Olax subscorpioidea, which is used in ethnomedicine to treat cancer, was subjected to phytochemical investigation leading to the isolation of oleanolic acid (OA). The structure was elucidated by 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopic (NMR) data, and by comparing its data with previously reported data. Molecular docking was used to investigate the interactions of OA with nine selected cancer-related protein targets. OA docked well with human 17β-hydroxysteroid dehydrogenase type-1 (17βHSD1), caspase-3, and epidermal growth factor receptor tyrosine kinase (binding affinities: −9.8, −9.3, and −9.1 kcal/mol, respectively). OA is a triterpenoid compound with structural similarity to steroids. This similarity with the substrates of 17βHSD1 gives the inhibitor candidate an excellent opportunity to bind to 17βHSD1. The structural and functional dynamics of OA-17βHSD1 were investigated by molecular dynamics simulations at 240 ns. Molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) studies showed that OA had a binding free energy that is comparable with that of vincristine (–52.76, and −63.56 kcal/mol, respectively). The average C-α root mean square of deviation (RMSD) value of OA (1.69 Å) compared with the unbound protein (2.01 Å) indicated its high stability at the protein’s active site. The binding energy and stability at the active site of 17βHSD1 recorded in this study indicate that OA exhibited profound inhibitory potential. OA could be a good scaffold for developing new anti-breast cancer drugs.

Revealing the molecular mechanism of baohuoside I for the treatment of breast cancer based on network pharmacology and molecular docking

Ethnopharmacological relevanceIn Traditional Chinese Medicine (TCM), there are many prescriptions for treating breast cancer (BC) that utilize the herb Epimedium brevicornum Maxim, which warms and replenishes kidney yang. Baohuoside I (BI) is a flavonoid compound found in Epimedium brevicornum Maxim. As a single glycoside, it is not easily hydrolyzed in the intestine and is typically absorbed as a precursor. As a natural product with potential anti-cancer properties, studies have shown that BI possesses anti-cancer activity and can inhibit the invasion and migration of BC cells. However, its underlying mechanisms remain unclear, thus further research is needed to validate its modern mechanisms for traditional uses. Aim of the studyThis study aimed to explore the regulatory mechanism of BI in the signaling pathways of BC cells through network pharmacology (NP), molecular docking (MD) techniques and cellular experiments. MethodsPotential targets were predicted using public databases, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Key signaling pathways were validated through MD techniques, cellular experiments, RNA interference and Western blot (WB) analysis. ResultsTreatment-associated targets included SRC, MAPK1, HSP90AA1, PIK3CA, TP53, AKT1, and EGFR. GO enrichment, KEGG enrichment analyses, and MD results indicated that BI exerts its anti-breast cancer effects by inhibiting the tyrosine kinase activity of EGFR, as well as through downstream MAPK signaling pathway and PI3K-Akt signaling pathway pathways. In vitro experiments confirmed that BI primarily induce cell apoptosis through the EGFR-mediated MAPK signaling pathway and PI3K-Akt signaling pathway. ConclusionBI can inhibit EGFR activation and promote BC cell apoptosis through the MAPK signaling pathway and PI3K-Akt signaling pathway, thereby exerting therapeutic effects on BC. This study not only provides experimental evidence for the accuracy of NP but also offers an effective approach for rational utilization of Baohuoside I-like flavonoid compounds as anti-breast cancer drugs.

Retraction Note: Investigating the Effects of Melittin-Loaded Pectin as Novel Anti Breast Cancer Drug to Increase the Apoptosis Rate

Retraction Note: Investigating the Effects of Melittin-Loaded Pectin as Novel Anti Breast Cancer Drug to Increase the Apoptosis Rate

A Study on the Binding Mechanism and the Impact of Key Residue Mutations between SND1 and MTDH Peptide through Molecular Dynamics Simulations.

Metastasis of breast cancer is the main cause of death for patients with breast cancer. The interaction between metadherin (MTDH) and staphylococcal nuclease domain 1 (SND1) plays a pivotal role in promoting breast cancer development. However, the binding details between MTDH and SND1 remain unclear. In this study, we employed all-atom molecular dynamics simulations (MDs) and conducted binding energy calculations to investigate the binding details and the impact of key residue mutations on binding. The mutations in key residues have not significantly affected the overall stability of the structure and the fluctuation of residues near the binding site; they have exerted a substantial impact on the binding of SND1 and MTDH peptide. The electrostatic interactions and van der Waals interactions play an important role in the binding of SND1 and the MTDH peptide. The mutations in the key residues have a significant impact on electrostatic and van der Waals interactions, resulting in weakened binding. The energy contributions of key residues mainly come from the electrostatic energy and van der Waals interactions of the side chain. In addition, the key residues form an intricate and stable network of hydrogen bonds and salt-bridge interactions with the MTDH peptide. The mutations in key residues have directly disrupt the interactions formed between SND1 and MTDH peptide, consequently leading to changes in the binding mode of the MTDH peptide. These analyses unveil the detailed atomic-level interaction mechanism between SND1 and the MTDH peptide, providing a molecular foundation for the development of antibreast cancer drugs.

Repositioning fluphenazine as a cuproptosis-dependent anti-breast cancer drug candidate based on TCGA database

Breast cancer is one of the most prevalent malignancies among women. Enhancing the prognosis is an effective approach to enhance the survival rate of breast cancer. Cuproptosis, a copper-dependent programmed cell death process, has been associated with patient prognosis. Inducing cuproptosis is a promising approach for therapy. However, there is currently no anti-breast cancer drug that induces cuproptosis. In this study, we repositioned the clinical drug fluphenazine as a potential agent for breast cancer treatment by inducing cuproptosis. Firstly, we utilized the Cancer Genome Atlas (TCGA) database and Connectivity Map (CMap) database to identify 22 potential compounds with anti-breast cancer activity through inducing cuproptosis. Subsequently, our findings demonstrated that fluphenazine effectively suppressed the viability of MCF-7 cells. Fluphenazine also significantly inhibited the viability of triple negative breast cancer cells MDA-MB-453 and MDA-MB-231. Furthermore, our study revealed that fluphenazine significantly down-regulated the expression of potential prognostic biomarkers associated with cuproptosis, increased copper ion levels, and reduced intracellular pyruvate accumulation. Additionally, it up-regulated the expression of FDX1 at both the mRNA and protein levels, which has been reported to play a crucial role in the induction of cuproptosis. These findings suggest that fluphenazine has the potential to be used as an anti-breast cancer drug by inducing cuproptosis. Therefore, this research provides an insight for the development of novel cuproptosis-dependent anti-cancer agents.

Lindqvist-type Polyoxometalates Act as Anti-breast Cancer Drugs via Mitophagy-induced Apoptosis.

Lindqvist-type polyoxometalates (POMs) exhibit potential antitumor activities. This study aimed to examine the effects of Lindqvist-type POMs against breast cancer and the underlying mechanism. Using different cancer cell lines, the present study evaluated the antitumor activities of POM analogues that were modified at the body skeleton based on molybdenum-vanadium-centered negative oxygen ion polycondensations with different side strains. Cell colony formation assay, autophagy detection, mitochondrial observation, qRT-PCR, Western blotting, and animal model were used to evaluate the antitumor activities of POMs against breast cancer cells and the related mechanism. MO-4, a Lindqvist-type POM linking a proline at its side strain, was selected for subsequent experiments due to its low half maximal inhibitory concentration in the inhibition of proliferation of breast cancer cells. It was found that MO-4 induced the apoptosis of multiple types of breast cancer cells. Mechanistically, MO-4 activated intracellular mitophagy by elevating mitochondrial reactive oxygen species (ROS) levels and resulting in apoptosis. In vivo, breast tumor growth and distant metastasis were significantly reduced following MO-4 treatment. Collectively, the results of the present study demonstrated that the novel Lindqvist-type POM MO-4 may exhibit potential in the treatment of breast cancer.

Optimized Modeling of Anti-Breast Cancer Drug Candidates

Optimized Modeling of Anti-Breast Cancer Drug Candidates

Novel pyrrole-chromone based chalcones: Synthesis and their anti-breast cancer activity: An in-silico study

Newer Pyrrole-Chromones Chalcones (I–VII) were prepared by a simple method. among the series of compounds, compound −1 which was synthesized with 30 % of NaOH solution, at temperature of 60–65 °C with twelve hours of reaction time resulted in good yield. While, the other compounds under same and varying conditions resulted in less yield. Existing reports showed that this group of compounds showed insulysin inhibition, interleukin antagonist, and membrane integrity agonist activities. The proteins EGFR and HER-2 which are over expressed in breast cancer, in In silico studies with the titled compounds showed strong binding affinity when compared to the standard drug tamoxifen, which clearly indicate that these compounds possess anti-breast cancer activity. Hence, it can be concluded that these compounds has the potential to develop as anti-breast cancer drugs.

Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure-Activity Relationships.

Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.

Investigating the potent TOPO IIα inhibitors in breast cancer through the study of computational drug discovery research approaches.

Breast cancer (BC) is the second-leading cause of cancer after lung cancer. The disease has affected millions of people and resulted in many deaths. In the metastasis of breast cancer cells, Topoisomerase IIα plays a vital role. Therefore, this investigation aims to identify potential flavonoid compounds against BC by inhibiting this enzyme at an early stage. Based on previous studies, we selected and screened several plant-derived flavonoid compounds with potential anti-breast cancer activity using PyRx 0.8 and Schrodinger applications for preliminary molecular docking: the highest docking scores of Myricetin (-11.6kcal/mol) and Quercetin (-10.0kcal/mol). Next, we evaluated the top four compounds on the Way2Drug server to complete the cytotoxicity evaluation, which demonstrated anti-cancer and anti-breast cancer activity in various cell lines. According to pharmacokinetics studies, four compounds exhibited outstanding values and functioned similar to drug-like molecules. Moreover, Myricetin, Quercetin, and Morin displayed the highest number of hydrogen bonds, with the corresponding receptor forming residues asn120, thr147, and lys168. The protein-ligand complexes were validated using the Desmond simulator, and their data were compared to the anti-breast cancer drug Doxorubicin. In the simulation analysis, various parameters were evaluated, including RMSD, RMSF, Rg, SASA, MolSA, PSA, and hydrogen bond interaction. Finally, validated our dynamic simulation result with MM-GBSA operation, and Myricetin and Quercetin had the greatest score of -72.74344651, -66.66771823kcal/mol, which is outstanding than the control drug. Hence, the computational research approach determined that Myricetin, Quercetin, and Morin could be industrially developed for the alternative treatment of breast cancer following additional confirmation from animal and cell line studies.

Discovery of acetophenone/piperazin-2-one hybrids as selective anti-TNBC cancer agents by causing DNA damage

Twenty-five acetophenone/piperazin-2-one (APPA) hybrids were designed and synthesized based on key pharmacophores found in anti-breast cancer drugs Neratinib, Palbociclib, and Olaparib. Compound 1j exhibited good in vitro antiproliferative activity (IC50 = 6.50 μM) and high selectivity (SI = 9.2 vs HER2-positive breast cancer cells SKBr3; SI = 7.3 vs normal breast cells MCF-10A) against triple negative breast cancer (TNBC) cells MDA-MB-468. In addition, 1j could selectively cause DNA damage, inducing the accumulation of γH2AX and P53 in MDA-MB-468 cells. It also reduced the phosphorylation level of P38 and the expression of HSP70, which further prevented the repair of DNA damage and caused cells S/G2-arrest leading to MDA-MB-468 cells death.

Synergistic Effect of Layered Double Hydroxides Nanodosage Form to Induce Apoptosis and Ferroptosis in Breast Cancer.

Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer. The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis. In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.