Combination Therapy For Breast Cancer Research Articles

Dual biomarkers-activatable hollow MnO2-Based theranostic nanoplatform for efficient breast cancer-specific multisite fluorescence imaging and synergistic therapy

BackgroundTheranostic nanoplatforms with integrated diagnostic imaging and multiple therapeutic functions play a vital role in precise diagnosis and efficient treatment for breast cancer, but unfortunately, these nanoplatforms are usually stuck in single-site imaging and single mode of treatment, causing unsatisfactory diagnostic and therapeutic efficiency. Herein, a dual biomarkers-activatable facile hollow mesoporous MnO2 (H–MnO2)-based theranostic nanoplatform, DNAzyme@H–MnO2-MUC1 aptamer (DHMM), was constructed for the simultaneous multi-site diagnosis and multiple treatment of breast cancer. ResultsThe DHMM acted as an integrated diagnostic and therapeutic nanoplatform that realizes multi-site fluorescence imaging-guided high-efficient photothermal/chemodynamic/gene synergistic therapy (PTT/CDT/GT) for breast cancer. The H–MnO2 exhibits high loading capacity for Cy5-MUC1 aptamer (3.05 pmoL μg−1) and FAM-DNAzyme (3.37 pmoL μg−1), and excellent quenching for the probes. In the presence of MUC1 on the cell membrane and GSH in the cytoplasm, Cy5-MUC1 aptamer and FAM-DNAzyme was activated triggering dual-channel fluorescence imaging at different sites. Moreover, the self-supplied Mn2+ was further supplied as DNAzyme cofactors to catalytic cleavage intracellular EGR-1 mRNA for high-efficient GT and stimulated the Fenton-like reaction for CDT. The H–MnO2 also showcases a favorable photothermal performance with a photothermal conversion efficiency of 44.16%, which ultimately contributes to multi-site fluorescence imaging-guided synergistic treatment with an apoptosis rate of 71.82%. SignificanceThis dual biomarker-activatable multiple therapeutic nanoplatform was realized multi-site fluorescence imaging-guided PTT/CDT/GT combination therapy for breast cancer with higher specificity and efficiency, which provides a promising theranostic nanoplatform for the precision and efficiency of breast cancer treatment.

Ginsenoside Rg3 overcomes tamoxifen resistance through inhibiting glycolysis in breast cancer cells.

Tamoxifen (TAM) resistance poses a significant clinical challenge in human breast cancer and exhibits high heterogeneity among different patients. Rg3, an original ginsenoside known to inhibit tumor growth, has shown potential for enhancing TAM sensitivity in breast cancer cells. However, the specific role and underlying mechanisms of Rg3 in this context remain unclear. Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model. In conclusion, this study highlights the contribution of Rg3 in enhancing the therapeutic efficacy of TAM in breast cancer, and suggests that targeting TAM-resistant PFKFB3 overexpression may represent a promising strategy to improve the response to combination therapy in breast cancer.

Discovery of Repurposable Drugs in the Combination Therapy of Breast Cancer: A Virtual Drug Screening Study

Cathepsin D (Cat D) is a lysosomal aspartic acid protease encoded by CTSD gene and has significant biological roles such as degradation of extracellular and intracellular proteins, regulation of apoptosis, hormone processing, antigen processing etc. Furthermore, it is overexpressed by breast cancer cells and it acts a role in many processes affecting the cancer prognosis such as metastasis, angiogenesis, invasion, and drug resistance through regulation of the metabolic pathways and digesting the extracellular matrix (ECM) proteins. Due to that there is no drug targeting Cat D in clinical trial phases, a virtual drug screening in order to reveal possible drugs with high Cat D inhibitory activity from a library composed of 12,111 ligands is carried out with this study. Results have demonstrated that ZINC000003922429 (Adozelesin), ZINC000012358610 (Phthalocyanine), ZINC000051951669 (Bemcentinib), ZINC000003786250 (YM022), and ZINC000150338819 (Ledipasvir) have high binding affinity to Cat D. Among these chemical ligands, YM022 from Drugs in Clinical Trials dataset has been evaluated as most promising one that might be repurposed in the treatment of breast cancer due to its high affinity, convenient ADME and Toxicity properties, and highest bioactivity profiles. However, the possible activity of YM022 should be analyzed with further molecular dynamics (MD) simulations, in vitro and in vivo studies.

Folate receptor-mediated delivery system based on chitosan coated polymeric nanoparticles for combination therapy of breast cancer

Combination therapy using two or more drugs with different mechanisms of action is an effective strategy for treating cancer. This is because of the synergistic effect of complementary drugs that enhances their effectiveness. However, this approach has some limitations, such as non-specific distribution of the drugs in the tumor and the occurrence of dose-dependent toxicity to healthy tissues. To overcome these issues, we have developed a folate receptor-mediated co-delivery system that improves the access of chemotherapy drugs to the tumor site. We prepared a nanoplatform by encapsulating paclitaxel (PTX) and curcumin (CUR) in poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone) (PCL-PEG-PCL) co-polymer using a double emulsion method and coating nanoparticles with pH-responsive chitosan-folic acid (CS-FA) conjugate. The nanocarrier’s physicochemical properties were studied, confirming successful preparation with appropriate size and morphology. PTX and CUR could be released synchronously in a controlled and acid-facilitated manner. The dual drug-loaded nanocarrier exhibited excellent anti-tumor efficiency in MDA-MB-231 cells in vitro. The active targeting effect of FA concluded from the high inhibitory effect of dual drug-loaded nanocarrier on MDA-MB-231 cells, which have overexpressed folate receptors on their surface, compared to Human umbilical vein endothelial cells (HUVEC). Overall, the nanoengineered folate receptor-mediated co-delivery system provides great potential for safe and effective cancer therapy.

Intelligent Nanoplatform Integrating Macrophage and Cancer Cell Membrane for Synergistic Chemodynamic/Immunotherapy/Photothermal Therapy of Breast Cancer.

Cell membrane-coated nanoplatforms for drug delivery have garnered significant attention due to their inherent cellular properties, such as immune evasion and homing abilities, making them a subject of widespread interest. The coating of mixed membranes from different cell types onto the surface of nanoparticles offers a way to harness natural cell functions, enhancing biocompatibility and improving therapeutic efficacy. In this study, we merged membranes from murine-derived 4T1 breast cancer cells with RAW264.7 (RAW) membranes, creating a hybrid biomimetic coating referred to as TRM. Subsequently, we fabricated hybrid TRM-coated Fe3O4 nanoparticles loaded with indocyanine green (ICG) and imiquimod (R837) for combination therapy in breast cancer. Comprehensive characterization of the RIFe@TRM nanoplatform revealed the inherent properties of both cell types. Compared to bare Fe3O4 nanoparticles, RIFe@TRM nanoparticles exhibited remarkable cell-specific self-recognition for 4T1 cells in vitro, leading to significantly prolonged circulation life span and enhanced in vivo targeting capabilities. Furthermore, the biomimetic RIFe@TRM nanoplatform induced tumor necrosis through the Fenton reaction and photothermal effects, while R837 facilitated enhanced uptake of tumor-associated antigens, further activating CD8+ cytotoxic T cells to strengthen antitumor immunotherapy. Hence, RIFe@TRM nanoplatform demonstrated outstanding synergy in chemodynamic/immunotherapy/photothermal therapies, displaying significant inhibition of breast tumor growth. In summary, this study presents a promising biomimetic nanoplatform for effective treatment of breast cancer.

In Vitro Evaluation of Cytotoxic and Antitumor Activities of The Tamoxifen and Doxorubicin Combination on MCF-7 and BT-474 Breast Cancer Cell Lines

The combination therapy of breast cancer has preferred for the patients to minimize possible side effects, drug resistance, recurrence and toxic effects. In this study, we aim to investigate the cytotoxic and antitumor activities the tamoxifen and doxorubicin combination in breast cancer cell lines, MCF-7 and BT-474. Tamoxifen (Tam) and doxorubicin (Dox) and their combination with different concentrations (0.625–20 μM Tam; 0.0625–2 μM Dox and 5 μM Tam+ 0.5/1.0/1.5 μM Dox combination were applied to MCF-7 and BT-474 cells for 48 hours. Afterthat, their cytotoxic activities were analyzed with MTT assay. Bcl-2, Mapt and Mrp1 are genes that induce cell proliferation, inhibit apoptosis and play role in drug resistance in cancer cells. To evaluate the antitumor activities of these genes in combination treatment, mRNA levels were analyzed by quantitative PCR. According to the MTT assay, it was determined that IC50 values as 17.26 μM and 16.65 μM for tamoxifen on MCF-7 and BT-474 breast cancer cell lines. IC50 values of doxorubicin in MCF-7 and BT-474 cells were 1.65 μM and 1.57 μM, respectively. It was found that the application of the combination drugs (15 μM tamoxifen and 1.5 μM doxorubicin) in MCF-7 and BT-474 cells have the lowest combination index values as 1.09 and 1.26, respectively. Therefore, the combination of 15 μM tamoxifen and 1.5 μM doxorubicin was selected and applied to both breast cancer cell lines for gene expression analysis. It was found that while Mrp1 and Mapt genes expressions were significantly upregulated, Bcl-2 gene expression was downregulated in MCF-7 cells. However, Bcl-2, Mrp1 and Mapt genes expressions in BT-474 cells were not significantly regulated. Altogether, these findings suggest that the combination of these two drugs may have a potential antagonistic interaction according combination index values.

One-pot synthesis of ultrasmall ferric ion coupled mitoxantrone nanoparticles for high bioavailability and effective chemo-ferroptosis combination therapy of breast cancer

Mitoxantrone (MIT) as a first line anticancer drug, is usually suffered from poor bioavailability upon in vivo application. Although previous studies have developed some carriers to improve its bioavailability, they also have the shortage of low drug loading and reproducibility. Herein, we proposed a facile one-pot method to synthesize ultrasmall ferric ion coupled mitoxantrone nanoparticles (Fe-MIT NPs) for effective therapy of breast cancer. The important finding includes: 1) The Fe-MIT NPs exhibited an average size of 40 nm with good dispersity and prolonged circulation in the bloodstream; 2) Fe-MIT NPs showed a high degree of accumulation within the tumor; 3) Fe-MIT NPs had a notable chemotherapy effect on cancer cells, which was achieved by increasing intracellular levels of reactive oxygen species (ROS); 4) The loaded Fe3+ within Fe-MIT NPs initiated ferroptosis through the Fenton reaction; 5) The ultrasmall size of the Fe-MIT NPs enabled better penetration of tumors. Therefore, when compared to free MIT, the Fe-MIT NPs delivered superior anticancer benefits. These benefits were observed in MCF-7 cells, MCF-7 multicellular tumor spheroids (MCTS), and MCF-7 tumor-bearing models.

Combined oncolytic virotherapy gold nanoparticles as synergistic immunotherapy agent in breast cancer control

Combining viruses and nanoparticles may be a way to successfully treat cancer and minimize adverse effects. The current work aimed to evaluate the efficacy of a specific combination of gold nanoparticles (GNPs) and Newcastle disease virus (NDV) to enhance the antitumor effect of breast cancer in both in vitro and in vivo models. Two human breast cancer cell lines (MCF-7 and AMJ-13) and a normal epithelial cell line (HBL-100) were used and treated with NDV and/or GNPs. The MTT assay was used to study the anticancer potentials of NDV and GNP. The colony formation assay and apoptosis markers were used to confirm the killing mechanisms of NDV and GNP against breast cancer cell lines. p53 and caspase-9 expression tested by the qRT-PCR technique. Our results showed that combination therapy had a significant killing effect against breast cancer cells. The findings demonstrated that NDV and GNPs induced apoptosis in cancer cells by activating caspase-9, the p53 protein, and other proteins related to apoptosis, which holds promise as a combination therapy for breast cancer.

Recent research and clinical progress of CTLA-4-based immunotherapy for breast cancer.

Breast cancer is characterized by a high incidence rate and its treatment challenges, particularly in certain subtypes. Consequently, there is an urgent need for the development of novel therapeutic approaches. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) is currently gaining momentum for the treatment of breast cancer. Substantial progress has been made in clinical studies employing cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors for breast cancer, but the cure rates are relatively low. To improve the efficacy of CTLA-4-based therapy for breast cancer, further research is imperative to explore more effective immune-based treatment strategies. In addition to monotherapy, CTLA-4 inhibitors are also being investigated in combination with other ICIs or alternative medications. However, it should be noted that immune-based treatments may cause adverse events. This review focuses on the mechanisms of CTLA-4 inhibitor monotherapy or combination therapy in breast cancer. We systematically summarize the latest research and clinical advances in CTLA-4-based immunotherapy for breast cancer, providing new perspectives on the treatment of breast cancer. In addition, this review highlights the immune-related adverse events (irAEs) associated with CTLA-4 inhibitors, providing insights into the development of appropriate clinical tumor immunotherapy regimens and intervention strategies.

MiR-138-5p improves the chemosensitivity of MDA-MB-231 breast cancer cell line to paclitaxel.

Chemotherapy is a predominant strategy for breast cancer (BC) treatment and paclitaxel (PTX) has been known as a conventional chemotherapeutic drug. However, insensitivity of BC cells to PTX limits the anti-tumor effects of this agent. MicroRNAs are closely related to BC which are suggested as therapeutic factors in the combination therapy of BC. We examined the possible efficacy of miR-138-5p restoration in combination with PTX to impove BC treatment. The human breast cancer cell line MDA-MB-231 was transfected with miR-138-5p mimics and treated with PTX, in a combined or separate manner. The MTT assay was accomplished to determine inhibitory doses of PTX. Annexin V/PI assay and DAPI staining were applied to evaluate apoptosis. Flow cytometry was applied to determine cells arrested in different phases of the cell-cycle. Expression levels of molecular factors involved in cell migration, proliferation, apoptosis, and cell cycle were determined via western blotting and qRT-PCR. MiR-138-5p combined with PTX suppressed cell migration via modulating MMP2, E-cadherin, and vimentin and sustained colony formation and proliferation by downregulation of the PI3K/AKT pathway. qRT-PCR showed that miR-138-5p increases BC chemosensitivity to PTX by regulating the apoptosis factors, including Bcl-2, Bax, Caspase 3, and Caspase 9. Moreover, miR-138-5p restoration and paclitaxel therapy combined arrest the cells in the sub-G1 and G1 phases of cell cycle by regulating p21, CCND1, and CDK4. Restored miR-138-5p intensified the chemosensitivity of MDA-MB-231 cell line to PTX, and the combination of miR-138-5p with PTX might represent a novel approach in BC treatment.

HB5 aptamer-tagged graphene oxide for co-delivery of doxorubicin and silibinin, and highly effective combination therapy in breast cancer

Using a chemotherapeutic agent, such as doxorubicin (DOX), with a natural agent, such as silibinin (Sili), is highly valuable to minimize systemic toxicity. However, Sili and DOX face disadvantages, such as low aqueous solubility and poor bioavailability. Here, we have engineered a drug delivery cargo by decorating carboxylated graphene oxide (cGO) with an aptamer, HB5, for simultaneous delivery of DOX and Sili as a combination therapy against MCF-7 and SK-BR-3 breast cancer cells. The resulting Apt-cGO displayed a typical sheet-like nanostructure with a broad surface. The maximum entrapment efficiency was 70.42% and 84.22% for Sili and DOX, respectively. When the Apt-cGO-DOX-Sili nanocomposites were selectively taken up by breast cancer cells, the interaction between cGO and drugs was cleaved, causing releasing both Sili and DOX into the tumor cells, respectively. Compared to free drugs, Apt-cGO-DOX-Sili nanocomposites displayed higher cytotoxicity in vitro. Apt-cGO-DOX-Sili nanocomposites potentially suppressed some cancer cell survival signals. They accelerated cell apoptosis and increased Rb levels as well as reduced Akt, mTOR, NF-κB, and CDK2 levels. In conclusion, the developed Apt-cGO-DOX-Sili can be suggested as a simple and efficient drug delivery approach for breast chemotherapy.

The activity and surface presence of organic cation/carnitine transporter OCTN2 (SLC22A5) in breast cancer cells depends on AKT kinase

l-carnitine is indispensable for transfer of fatty acids to mitochondria for the process of β-oxidation, a process, whose significance in cancer has drawn attention in recent years. In humans majority of carnitine is delivered by diet and enters the cell due to activity of solute carriers (SLCs), mainly by ubiquitously expressed organic cation/carnitine transporter (OCTN2/SLC22A5). In control and cancer human breast epithelial cell lines the major fraction of OCTN2 is present as a not matured non-glycosylated form. Studies on overexpressed OCTN2 demonstrated an exclusive interaction with SEC24C, as the cargo-recognizing subunit of coatomer II in transporter exit from endoplasmic reticulum. Co-transfection with SEC24C dominant negative mutant completely abolished presence of the mature form of OCTN2, pointing to a possibility of trafficking regulation. SEC24C was previously shown to be phosphorylated by serine/threonine kinase AKT, known to be activated in cancer. Further studies on breast cell lines showed that inhibition of AKT with MK-2206 in control and cancer lines decreased level of OCTN2 mature form. Proximity ligation assay showed that phosphorylation of OCTN2 on threonine was significantly abolished by AKT inhibition with MK-2206. Carnitine transport was positively correlated with the level of OCTN2 phosphorylated by AKT on threonine moiety. The observed regulation of OCTN2 by AKT places this kinase in the center of metabolic control. This points to both proteins, AKT and OCTN2, as druggable targets, in particular in a combination therapy of breast cancer.

Abstract 2785: Carbidopa/α-methyltryptophan as an ideal combination therapy for breast cancer

Abstract Background/Hypothesis: The amino acid transporter SLC6A14 is upregulated in estrogen receptor (ER)-positive breast cancer, a subtype that represents 75-80% of all breast cancers. Obesity/overweight increases the risk of breast cancer due to estrogen generated from fat cells that fuel the growth of the ER-positive breast cancer. Previous studies from our lab have demonstrated that blockade of the amino acid transporter SLC6A14 by the small molecule α-methyltryptophan reduces the growth of ER-positive breast cancer in mouse xenografts of human breast cancer cells and in a spontaneous mouse model of ER-positive breast cancer. We have also discovered that α-methyltryptophan functions as a potent weight-loss agent. We believe that this compound would be effective for the treatment of ER-positive breast cancer, especially in obese/overweight women. α-methyltryptophan is metabolized by aromatic amino acid decarboxylase. Therefore, combination of this compound with carbidopa, a well-known inhibitor of this enzyme, might potentiate the anticancer efficacy of α-methyltryptophan. We tested this idea in the present study using a syngeneic mouse model of ER-positive breast cancer using the mouse breast cancer cell line AT3. Results: A syngeneic tumor-cell transplant mouse model was used for ER-positive breast cancer. AT3 cells were injected into the mammary fat pad of C57BL/6 mice. This allows to monitor the growth of AT3 tumor growth in an immunologically competent mammary tissue environment. Drug treatment in drinking water was started after tumor growth was noticeable (100 mm3). There were four groups: (i) control; (ii) α-methyltryptophan at 0.5 mg/ml; (iii) carbidopa at 0.25 mg/ml; (iv) α-methyltryptophan at 0.5 mg/ml + carbidopa at 0.25 mg/ml. Tumor growth was monitored every three days. The mice were killed after 4 weeks of treatment. Tumors were excised and weighed. These studies showed that α-methyltryptophan and carbidopa were independently effective in reducing the tumor (48% reduction, p<0.05 for α-methyltryptophan; 50% reduction, p<0.05 for carbidopa), but the combination was the most effective (92% reduction, p<0.01). These effects were evident irrespective of whether the monitored parameter was tumor weight or tumor volume. Conclusion: The combination treatment significantly decreased the tumor size and volume compared to carbidopa and α-methyltryptophan alone. We do not know yet if the improved efficacy of the combination of the two drugs is due to a simple additive effect or due to a synergistic effect. Studies have shown that carbidopa promotes degradation of ER, indicating that carbidopa has its own independent anticancer effect that is relevant to ER-positive breast cancer. Further studies are needed to differentiate between the effect of carbidopa as an independent anticancer agent and its ability to potentiate the anticancer efficacy of α-methyltryptophan by preventing its metabolic degradation. Citation Format: Sirin Falconi, Sabarish Ramachandran, Vadivel Ganapathy. Carbidopa/α-methyltryptophan as an ideal combination therapy for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2785.

Preparation of polydopamine-based concave nanoparticles and mild photothermal-anti-inflammatory combination therapy for breast cancer guided by magnetic resonance imaging

Photothermal therapy (PTT) has been widely investigated as a regimen for superficial tumors. However, conventional PTT strategies usually require photothermal temperatures above 50 °C to achieve significant therapeutic efficacy, which in effect would lead to injury to adjacent normal tissues and meanwhile, the heat generated by the photothermal effect would induce inflammation owing to the damage to cytoplasmic components. In order to reduce the toxicity of photothermal therapy and increase the efficiency of photothermal tumor destruction, novel strategies are prerequisite for targeted regimen and surveillance of photothermal therapy in real time. In this paper, we reported a concave mesoporous polydopamine-targeting nanotherapeutic agent. We employed B-MPDA as the carrier and encapsulated CQ and ASP to yield B-MPDA/CQ/ASP which was loaded with autophagy inhibitors and anti-inflammatory agents and coated uniformly with MnO2 Nanosheet. With HA functionalizing MnO2 Nanosheet, B-MPDA/CQ/ASP@MnO2-HA was constituted. The yielded nanoparticles were identified to be advantageous for good biocompatibility, potent targeting and low toxicity. In anti-tumor regimens, the nanoparticles can be applied to hyaluronic acid targeting, mesoporous polydopamine thermotherapy, and autophagy inhibitor sensitization thermotherapy, and simultaneously eliminate the inflammatory effects induced by photothermal therapy. Furthermore, in combination with the anti-inflammatory effect of targeting tumor, this agent can effectively induce apoptosis of cancer cells and significantly improve the efficiency of mild photothermal killing of cancer cells, which provides insight into the development of nanoparticles and application to mild photothermal therapy in the clinical scenario.

Icaritin Derivative IC2 Induces Cytoprotective Autophagy of Breast Cancer Cells via SCD1 Inhibition.

Breast cancer is one of the most prevalent malignancies and the leading cause of cancer-associated mortality in China. Icaritin (ICT), a prenyl flavonoid derived from the Epimedium Genus, has been proven to inhibit the proliferation and stemness of breast cancer cells. Our previous study demonstrated that IC2, a derivative of ICT, could induce breast cancer cell apoptosis by Stearoyl-CoA desaturase 1 (SCD1) inhibition. The present study further investigated the mechanism of the inhibitory effects of IC2 on breast cancer cells in vitro and in vivo. Our results proved that IC2 could stimulate autophagy in breast cancer cells with the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling and mitogen-activated protein kinase (MAPK) signaling. Combination treatment of the AMPK inhibitor decreased IC2-induced autophagy while it markedly enhanced IC2-induced apoptosis. In common with IC2-induced apoptosis, SCD1 overexpression or the addition of exogenous oleic acid (OA) could also alleviate IC2-induced autophagy. In vivo assays additionally demonstrated that IC2 treatment markedly inhibited tumor growth in a mouse breast cancer xenograft model. Overall, our study was the first to demonstrate that IC2 induced cytoprotective autophagy by SCD1 inhibition in breast cancer cells and that the autophagy inhibitor markedly enhanced the anticancer activity of IC2. Therefore, IC2 was a potential candidate compound in combination therapy for breast cancer.

Histone deacetylase inhibitors promote breast cancer metastasis by elevating NEDD9 expression

Histone deacetylase (HDAC) is a kind of protease that modifies histone to regulate gene expression, and is usually abnormally activated in tumors. The approved pan-HDAC inhibitors have demonstrated clinical benefits for patients in some hematologic malignancies. Only limited therapeutic success in breast cancer has been observed in clinical trials. In this study, we declare that pan-HDAC inhibitors targeting NEDD9-FAK pathway exacerbate breast cancer metastasis in preclinical models, which may severely impede their clinical success. NEDD9 is not an oncogene, however, it has been demonstrated recently that there are high level or activity changes of NEDD9 in a variety of cancer, including leukemia, colon cancer, and breast cancer. Mechanistically, pan-HDAC inhibitors enhance H3K9 acetylation at the nedd9 gene promoter via inhibition of HDAC4 activity, thus increase NEDD9 expression, and then activate FAK phosphorylation. The realization that pan-HDAC inhibitors can alter the natural history of breast cancer by increasing invasion warrants clinical attention. In addition, although NEDD9 has been reported to have a hand in breast cancer metastasis, it has not received much attention, and no therapeutic strategies have been developed. Notably, we demonstrate that FAK inhibitors can reverse breast cancer metastasis induced by upregulation of NEDD9 via pan-HDAC inhibitors, which may offer a potential combination therapy for breast cancer.

Recent advances and prospects of metal-organic frameworks in cancer therapies.

Metal-organic frameworks (MOFs) have been broadly applied in biomedical and other fields. MOFs have high porosity, a large comparative area, and good biostability and have attracted significant attention, especially in cancer therapies. This paper presents the latest applications of MOFs in chemodynamic therapy (CDT), sonodynamic therapy (SDT), photodynamic therapy (PDT), photothermal therapy (PTT), immunotherapy (IT), and combination therapy for breast cancer. A combination therapy is the combination of two different treatment modalities, such as CDT and PDT combination therapy, and is considered more effective than separate therapies. Herein, we have also discussed the advantages and disadvantages of combination therapy in the treatment of breast cancer. This paper aims to illustrate the potential of MOFs in new cancer therapeutic approaches, discuss their potential advantages, and provide some reflections on the latest research results.

Drug self-framework delivery system-coated gold nanorods for multi-modal imaging and combination therapy for breast cancer.

Herein, we report a multifunctional nanodrug (Au NRs@DSFDSs NPs) by coating a drug self-framework delivery system (DSFDS) on Au NRs with absorption at 1300 nm via simple condensation polymerization, with the purpose of developing an efficient theranostic nanoagent with multi-modal imaging ability, and synergistic chemo-photothermal therapy (CT-PTT) for the monitoring and suppression of tumor growth. Thus, this strategy provides a new idea for the design of a multifunctional platform for the accurate and effective image-guided treatment of tumors.

A copper nanocluster-based multifunctional nanoplatform for augmented chemo/chemodynamic/photodynamic combination therapy of breast cancer

With the development of nano drug delivery system, the treatment mode that can overcome the shortcomings of chemotherapy drugs and integrate combined therapy remains to be explored. Herein, a nano drug system was designed to achieve the combined effect of chemo/chemodynamic/photodynamic therapy on cancer. Specifically, copper clusters (CuNCs) were used as the carrier, hyaluronic acid (HA) and doxorubicin (DOX) were coupled on CuNCs and then and chlorin e6 (Ce6) was introduced to form the self-assembled HA-CuNCs@DC nanoparticles. In this system, the HA-CuNCs@DC was involved in the reaction to the acidic tumor microenvironment (TME)-release of DOX, which could not only inhibit tumor growth through chemotherapy, but enhance the generation of hydrogen peroxide. CuNCs carriers had the properties of Fenton-like activity to realize chemodynamic therapy (CDT) and oxidase-like activity to deplete intracellular glutathione (GSH). Additionally, the chemotherapy drug susceptibility increased owing to the GSH depletion and the outbreak of reactive oxygen species, indicating the enhanced CDT efficacy and amplified chemotherapy efficacy. It was also noteworthy that Ce6 could be activated by 660 nm light to produce abundant singlet oxygen for photodynamic therapy. Overall, our platform demonstrated excellent biosafety and tumor suppression capabilities. This multimodal theranostic strategy provided new insights into cancer therapy.

Codelivery of π-π Stacked Dual Anticancer Drugs Based on Aloe-Derived Nanovesicles for Breast Cancer Therapy.

To overcome the low efficacy of conventional monotherapeutic approaches that use a single drug, functional nanocarriers loaded with an amalgamation of anticancer drugs have been promising in cancer therapy. Herein, aloe-derived nanovesicles (gADNVs) are modified with an active integrin-targeted peptide (Arg-Gly-Asp, RGD) by the postinsertion technique to deliver indocyanine green (ICG) and doxorubicin (DOX) for efficient breast cancer therapy. We presented for the first time that the π-π stacking interaction can turn the "competitive" relationship of ICG and DOX inside gADNVs into a "cooperative" relationship and enhance their loading efficiency. The dual-drug codelivery nanosystem, denoted as DIARs, was well stable and leakproof, exhibiting high tumor-targeting capability both in vitro and in vivo. Meanwhile, this nanosystem showed significant inhibition of cell growth and migration and induced cell apoptosis with the combination of phototherapy and chemotherapy. Intravenous administration of DIARs exhibited high therapeutic efficacy in a 4T1 tumor-bearing mouse model and exhibited no obvious damage to other organs. Overall, our DIAR nanosystem constitutively integrated the natural and economical gADNVs, π-π stacking interaction based on efficient drug loading, and tumor-targeted RGD modification to achieve an effective combination therapy for breast cancer.