In Vitro Examinations of Cell Death Induction and the Immune Phenotype of Cancer Cells Following Radiative-Based Hyperthermia with 915 MHz in Combination with Radiotherapy

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA‑MB‑231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5–15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.

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Evaluation of the cytotoxic potential of extracts from the genus Passiflora cultived in Brazil against cancer cells

10.1101/337253 ◽

2018 ◽

Author(s):

Ricardo Guimarães Amaral ◽

Silvana Vieira Floresta Gomes ◽

Ângelo Roberto Antoniolli ◽

Maria Claudia dos Santos Luciano ◽

Cláudia do Ó Pessoa ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cytotoxic Activity ◽

Cancer Cells ◽

Tumor Cells ◽

Cytotoxic Potential ◽

Leaf Extracts ◽

High Cytotoxic Activity ◽

Apoptosis And Necrosis

AbstractThis work aimed to evaluate the cytotoxic potential against cancer cells of Passiflora genus plant species cultivated in Brazil and identify the mechanism of cytotoxicity induced by the most promising extract. Leaf extracts from 14 Passiflora (P.) species were obtained ASE and in vitro cytotoxicity evaluated against cancer cell lines using MTT assay at a single concentration of 50 μg/mL. Additionally, the IC50 of the P. alata (ELPA) leaf extracts was determined against both tumor (HCT-116, SF-295, OVACAR-8, and HL-60), and non-tumor cells (PBMC). The ELPA flavonoids were identified by HPLC-DAD and UHPLC-MS/MS. The morphological analyses used light and fluorescence microscopy, and cell cycle and DNA fragmentation analyses used flow cytometry to determine the mechanism of cell death induced by ELPA in HL-60. Among the Passiflora leaf extracts evaluated; ELPA stood out with high cytotoxic activity, followed by P. capsularis and P. quadrangulares with varying high and low cytotoxic activity. ELPA presented high cytotoxic potency in HL-60 (IC50 19.37 μg/mL), yet without cytotoxic activity against PBMC, suggesting selectivity for tumor cells. The cytotoxic activity of ELPA may well be linked to the presence of ten identified flavonoids. Cells treated with ELPA presented the hallmarks typical of apoptosis and necrosis, with cell cycle arrest in the G2/M phase. Conclusion: From among the studied species, ELPA presented greater cytotoxic activity, possibly a consequence of synergistic flavonoid action which induces cell death by apoptosis and necrosis.

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Dual-Function Anti-CD47mAbs Induce Tumor Cell Death and Promote Phagocytosis Resulting in Enhanced in Vivo Efficacy

Blood ◽

10.1182/blood.v124.21.991.991 ◽

2014 ◽

Vol 124 (21) ◽

pp. 991-991

Author(s):

Pamela T. Manning ◽

Benjamin J. Capoccia ◽

Michael P. Rettig ◽

Ronald R. Hiebsch ◽

Robert W. Karr ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Tumor Cells ◽

Tumor Burden ◽

Dual Function ◽

Employment Equity ◽

Hematologic Cancer ◽

Equity Ownership

Abstract Recent success in immunomodulation of cancer has targeted immune checkpoints such as CTLA-4, PD-1 and PDL-1 to enhance adaptive immunity by stimulating production of tumor-selective, cytotoxic T cells. Anti-CD47mAbs enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages leading to processing and presentation of tumor antigens to prime the adaptive T cell response. Many cancers, including hematologic cancers, up-regulate the expression of CD47 presumably to avoid immune destruction. Increased CD47 expression protects cancer cells from phagocytosis by sending a “don't eat me” signal to macrophages via SIRPalpha, an inhibitory receptor that prevents phagocytosis of CD47-bearing cells. CD47mAbs that block the CD47/SIRPalpha interaction (“blocking-only” mAbs) enhance phagocytosis of cancer cells in vitro. We have identified two CD47mAbs, Vx-1000 and Vx-1004, both of which block the CD47/SIRPalpha interaction and promote phagocytosis of tumor cells by macrophages equally well. However, Vx-1004 also has the unique property of killing cancer cells, but not normal blood cells, via a direct, cell-autonomous, cytotoxic mechanism. Therefore, Vx-1004 is a dual-function antibody. Vx-1004 selectively kills a variety of hematologic cancer cells in vitro, while Vx-1000, the blocking-only mAb, does not as assessed by annexin V staining and flow cytometry (Figure 1). In dose-response studies, cell death in leukemia cells was induced in 2 hrs by <1 ug="" vx-1004="" whereas="" normal="" peripheral="" blood="" mononuclear="" cells="" are="" resistant="" to="" the="" induction="" of="" cell="" death="" by="" following="" incubation="" with="" 10="" for="" 24="" hrs="" both="" these="" cd47mabs="" bind="" many="" species="" cd47="" including="" mouse="" and="" human="" p=""> To determine if the tumor-toxic activity of Vx-1004 confers enhanced efficacy in vivo compared to Vx-1000, we compared them in two mouse hematologic cancer models: murine acute promyelocytic leukemia (APL) and B cell lymphoma (BCL). Briefly, 1x106 GFP-labeled C57BL/6 APL cells were injected IV into wild-type C57BL/6 mice that were then treated IP with 0.4 mg/kg of either Vx-1000 or Vx-1004 on the day of tumor injection and on days 3 and 6 following tumor injection, a very low dose and limited dosing regimen. On day 25, the blood of these mice was analyzed for the number of circulating APL cells. As shown in Figure 2, Vx-1000 did not significantly reduce tumor burden compared to the control group. In contrast, Vx-1004 significantly reduced tumor burden compared to controls, demonstrating greater efficacy of the dual-function CD47mAb. In addition, enhanced efficacy of Vx-1004 compared to Vx-1000 was demonstrated in BCL (Figure 3). In this model, NSG mice were injected with 1x106 murine A20 lymphoma cells subcutaneously and then treated with 0.4mg/kg/day of the CD47mAbs IP for the first five days following tumor injection. In this model, Vx-1000 also failed to inhibit tumor growth compared to controls while Vx-1004 significantly reduced tumor burden at 35 days compared to both the control and Vx-1000 groups, nearly four weeks after treatment was stopped. These data demonstrate increased anti-cancer efficacy with a dual-function CD47mAb that not only blocks the CD47/SIRPalpha interaction to increase phagocytosis of cancer cells, but also selectively kills cancer cells. These studies indicate that dual-function CD47mAbs may have better anti-tumor activity in vivo and support their use in human clinical trials. Figure 1 Figure 1. Disclosures Manning: Corvus Pharmaceutical: Employment, Equity Ownership. Capoccia:Corvus Pharmaceutical: Employment, Equity Ownership. Hiebsch:Corvus Pharmaceutical: Employment, Equity Ownership. Karr:Corvus Pharmaceutical: Employment, Equity Ownership. Frazier:Corvus Pharmaceutical: Consultancy, Equity Ownership.

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Adaptive Antitumor Immune Response Stimulated by Bio-nanoparticle Based Vaccine and Checkpoint Blockade

10.21203/rs.3.rs-966722/v1 ◽

2021 ◽

Author(s):

Xuewei Bai ◽

Yanmei Zhou ◽

Yuki Yokota ◽

Yoshihiro Matsumoto ◽

Bo Zhai ◽

...

Keyword(s):

Immune Response ◽

Cancer Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Adaptive Immune Response ◽

Control Group ◽

Lymphoid Structures

Abstract Background: Interactions between tumor and microenvironment determines the response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors. Aspartate beta-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods: Orthotopic TNBC and subcutaneous HCC murine models were established. Immunohistochemistry, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based vaccine targeting ASPH was administrated to BALB/c mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In the control group, autocrine CXCL13-CXCR5 axis promoted cancer development and progression. Inhibition between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis. In contrast, combination therapy significantly suppressed primary hepatic or mammary tumor growth with distant pulmonary metastases in TNBC. An adaptive immune response was attributed to expansion of activated CD4+ Th1/CD8+ CTLs with enhanced effector function and high titers of ASPH-specific antibody. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), which secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, the presence of TLSs predicts sensitivity to immune checkpoint inhibitor blockade. Conclusions: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH combined with an immune checkpoint inhibitor represents a new approach for TNBC and HCC.

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Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

10.1101/2021.09.27.461902 ◽

2021 ◽

Author(s):

Boah Lee ◽

Seung Ju Park ◽

Seulgi Lee ◽

Jinwook Lee ◽

Eun Byeol Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cancer Treatment ◽

Cancer Cells ◽

Immune Checkpoint ◽

Therapeutic Option ◽

Cholesterol Lowering ◽

Cellular Environment ◽

Lowering Drug

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC-38 or B16-F10 pre-clinical syngeneic tumor models. These results elucidates the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

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Patterns of Cell Death Induced by Thiohydantoins in Human MCF-7 Breast Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210811102441 ◽

2021 ◽

Vol 21 ◽

Author(s):

Tatiane Renata Fagundes ◽

Bruna Bortoleti ◽

Priscila Camargo ◽

Vírgínia Concato ◽

Fernanda Tomiotto-Pellissier ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Death ◽

Cancer Cells ◽

Cell Volume ◽

Tumor Cells ◽

Breast Tumor ◽

Breast Cancer Cells ◽

Breast Tumor Cells ◽

Mcf 7

Background: Conventional therapies for breast cancer is still a challenge due to use of cytotoxic drugs not highly effective with major adverse effects. Thiohydantoins, are biologically active heterocyclic compounds reported by several biological activities, including anticarcinogenic properties, i.e., this work aimed to assess the use of thiohydantoin as a potential antitumor agent against MCF-7 breast cancer cells. Methods: MTT and neutral red assays were used to assess the possible cytotoxic activity of compounds against MCF-7 cells. Cell volume measurement and analysis were performed by flow cytometry, fluorescence analysis was carried out to determine patterns of cell death induced by thiohydantoins. Results: The treatment with micromolar doses of thiohydantoins promoted a decrease in the viability of MCF-7 breast tumor cells. Also were observed the increase in ROS and NO production, reduction in cell volume, loss of membrane integrity, mitochondrial depolarization, and increased fluorescence for annexin V and caspase-3. These findings indicate cell death by apoptosis and increased formation of autophagic vacuoles and stopping the cell cycle in the G1/ G0 phase. Conclusions: Our results indicate that thiohydantoins are cytotoxic to breast tumor cells, and this effect is linked to the increase in ROS production. This phenomenon changes tumorigenic pathways, that lead to a halt of the cell cycle in G1/G0, an important checkpoint for DNA errors, which may have altered the process by which cells produce energy, causing a decrease in mitochondrial viability and thus leading to the apoptotic process. Furthermore, the results indicate increased autophagy, a vital process linked to a decrease in lysosomal viability and considered as a cell death and tumor suppression mechanism.

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CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.79 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 79-79 ◽

Cited By ~ 7

Author(s):

Limo Chen ◽

Lauren Averett Byers ◽

Stephen Ullrich ◽

Ignacio Ivan Wistuba ◽

Xiao-Feng Qin ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cells ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

High Rate ◽

Positive Staining ◽

Antibody Treatment ◽

Mechanism Of Resistance

79 Background: Although immune checkpoint inhibitors including PD-L1 blockade provide significant clinical benefit for patients with lung cancer, barriers to immunotherapy clinical successes have been due to a high rate of resistance. The therapeutic improvement requires a thorough understanding of the biological process of resistance. Until recently, there have been only a few studies reporting the mechanisms of resistance to PD-L1 blockade. The mechanistic basis remains poorly defined. Methods: In multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the resistance mechanisms using pharmacological and genetic approaches (monoclonal antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to determine the applicability to patients with lung cancer, we analyzed 259 patients specimens with IHC staining and mined many immune markers in TCGA adeno and squamous datasets. Results: We identified the up-regulation of CD38 on tumor cells as well as enrichment of CD38highTregs and CD38highMDSCs in tumor as the markers of treatment resistance. We observed the same resistance mechanism caused by CD38 in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors edited with the CRISPR/Cas9 system. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines, in vitro and in vivo data demonstrates that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability. To test whether CD38 blockade might be therapeutically efficacious to anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in 259 lung patients, 18.5% of cases exhibited positive staining for CD38 on tumor cells, showing a great potential benefit for treating lung patients. Conclusions: CD38 is defined as a novel immune checkpoint and acts as a mechanism of resistance in the context of PD-L1 therapy. Targeting this novel immune checkpoint may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.

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Anticancer Activity and Apoptosis Induction of Gold(III) Complexes Containing 2,2′-Bipyridine-3,3′-Dicarboxylic Acid and Dithiocarbamates

Molecules ◽

10.3390/molecules26133973 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3973

Author(s):

Ali Alhoshani ◽

Adam A. A. Sulaiman ◽

Homood M. As Sobeai ◽

Wajhul Qamar ◽

Moureq Alotaibi ◽

...

Keyword(s):

Cell Death ◽

Dicarboxylic Acid ◽

Cancer Cells ◽

Elemental Analysis ◽

Spectroscopic Techniques ◽

Apoptosis Induction ◽

Induction Of Apoptosis ◽

Cytotoxic Studies ◽

Mcf 7

Three novel gold(III) complexes (1–3) of general composition [Au(Bipydc)(S2CNR2)]Cl2 (Bipydc = 2,2′-bipyridine-3,3′-dicarboxylic acid and R = methyl for dimethyldithiocarbamate (DMDTC), ethyl for diethyldithiocarbamate (DEDTC), and benzyl for dibenzyldithiocarbamate (DBDTC)) have been synthesized and characterized by elemental analysis, FTIR and NMR spectroscopic techniques. The spectral results confirmed the presence of both the Bipydc and dithiocarbamate ligands in the complexes. The in vitro cytotoxic studies demonstrated that compounds 1–3 were highly cytotoxic to A549, HeLa, MDA-231, and MCF-7 cancer cells with activities much higher (about 25-fold) than cisplatin. In order to know the possible mode of cell death complex 2, [Au(Bipydc)(DEDTC)]Cl2 was further tested for induction of apoptosis towards the MCF-7 cells. The results indicated that complex 2 induces cell death through apoptosis.

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Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma

Cancers ◽

10.3390/cancers13153676 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3676

Author(s):

Mengshi Li ◽

Dijie Liu ◽

Dongyoul Lee ◽

Yinwen Cheng ◽

Nicholas J. Baumhover ◽

...

Keyword(s):

Cell Death ◽

Tumor Growth ◽

Immune Checkpoint ◽

Radionuclide Therapy ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

The Body ◽

Immune Recognition

Radiotherapy can facilitate the immune recognition of immunologically “cold” tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically “cold” tumors throughout the body responsive to ICIs and immunologically “hot”. Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

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Decreas of BCL-2 Expression by Ethanol Extract of Ocinum basilicum L. Leaves in Breast Cancer Cells

Jurnal Profesi Medika Jurnal Kedokteran dan Kesehatan ◽

10.33533/jpm.v15i1.2491 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Devi Nisa Hidayati ◽

Fatimatuz Zahroh ◽

Lina Wahyuni ◽

Ibrahim Arifin

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Protein Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Ethanol Extract ◽

Ocimum Basilicum ◽

Protein Expressions ◽

Mcf 7

Ocimum basilicum L has proven to have in vitro cytotoxic activity against breast cancer cells. Pathways that cause cell death can involve one of the proteins, which is BCL-2. This study aims to determine the decrease of BCL-2 protein expressions in breast cancer cells (T47D and MCF-7) tat are treated with the ethanol extract of Ocimum basilicum L. Ocimum basilicum L. was extracted using the maceration method with 70% ethanol solvent. The concentration of ethanol extract of Ocimum basilicum L. used to see the expression of BCL-2 protein in T47D and MCF-7 cells was 199 µg/ml and 388 µg / mL. The observation of BCL-2 protein expression is using immunocytochemical methods of T47D and MCF-7 cancer cells. The results showed that the ethanol extract of Ocimum basilicum L could reduce BCL-2 protein expression in breast cancer cells (T47D and MCF-7) at concentrations of 199 µg/ml and 388 µg/ml, respectively.

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Enhanced Anticancer Property of Ad-MSC-TRAIL on Breast Cancer Cells When Combined with the Aqueous Extract of Berberis vulgaris

Jentashapir Journal of Cellular and Molecular Biology ◽

10.5812/jjcmb.107951 ◽

2020 ◽

Vol 11 (2) ◽

Author(s):

Mahdieh Khorashadizadeh ◽

Nahid Khazaei Moghadam ◽

Nasrin Zandi Dasht-e-Bayaz ◽

Mohsen Khorashadizadeh

Keyword(s):

Breast Cancer ◽

Combination Therapy ◽

Cancer Cells ◽

Tumor Cells ◽

Aqueous Extract ◽

Cancer Cell Line ◽

Expression Vectors ◽

Berberis Vulgaris ◽

Mcf 7

Background: Although there are improvements in breast cancer diagnosis and treatment methods, some breast tumor cells still are resistant to current therapies. Thus, there are attempts all over the world to find an effective way with more toxicity to tumor cells and less to normal cells. In recent years, mesenchymal stem cells (MSCs), due to their native tumor homing property, have been introduced as expression vectors for anticancer proteins, such as TNF-related apoptosis-inducing ligand (TRAIL). However, most tumor cells are resistant to TRAIL or show low sensitivity to it. Thus, it is necessary to find a way to increase the sensitivity of cancer cells and decrease their resistance. One of these ways is combination therapy with herbal drugs. Objectives: This study aimed to investigate the combination of sub-toxic doses of aqueous extract of Berberis vulgaris (AEBV) and MSC-TRAIL on MCF-7 cells as a human breast cancer cell line. Methods: Experiments were set based on in vitro cell culture. Combination therapy was carried out in transwell co-culture plates. The cell viability was determined by the MTT assay. The cell cycle was measured using the Propidium Iodide (PI) staining flow cytometry method. All experiments were performed in triplicate. The data were analyzed by One-way ANOVA test using SPSS software. Results: MCF-7 cells were relatively resistant to MSC-TRAIL and AEBV alone, while a sub-toxic concentration of AEBV (0.5 mg/mL) combined with MSC-TRAIL significantly increased death in MCF-7 cells, showing a synergistic effect.

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