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Oncolytic Herpes Simplex Virus and Temozolomide Synergistically Inhibit Breast Cancer Cell Tumorigenesis in Vitro and in Vivo

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Oncolytic Herpes Simplex Virus and Temozolomide Synergistically Inhibit Breast Cancer Cell Tumorigenesis in Vitro and in Vivo ONCOLOGY LETTERS 21: 99, 2021 Oncolytic herpes simplex virus and temozolomide synergistically inhibit breast cancer cell tumorigenesis in vitro and in vivo JINGJING FAN1*, HUA JIANG2*, LIN CHENG2, BINLIN MA1 and RENBIN LIU2 1Department of Breast and Neck Surgery, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang 830011; 2Breast Cancer Center, Department of Breast and Thyroid Surgery, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China Received October 14, 2019; Accepted September 23, 2020 DOI: 10.3892/ol.2020.12360 Abstract. The oncolytic herpes simplex virus (HSV) G47Δ TMZ alone. Synergy between G47Δ and TMZ was at least can selectively eliminate glioblastoma cells via viral replica‑ partially mediated via TMZ‑induced acceleration of G47Δ tion and temozolomide (TMZ) has been clinically used to replication, and such a synergy in breast cancer cells in vitro treat glioblastoma. However, the combined effect of G47Δ and in vivo provides novel insight into the future development and TMZ on cancer cells, particularly on breast cancer of a therapeutic strategy against breast cancer. cells, remains largely unknown. The objective of the present study was to investigate the role and underlying mechanism Introduction of G47Δ and TMZ, in combination, in breast cancer cell tumorigenesis. The human breast cancer cell lines SK‑BR‑3 Breast cancer is the most common life‑threatening cancer in and MDA‑MB‑468 were treated with G47Δ and TMZ indi‑ women globally, with an annual rate of new cases reaching vidually or in combination. Cell viability, flow cytometry, 126/100,000 women and a death rate of ~30% (1). Although reverse transcription quantitative‑PCR and western blotting conventional treatment options, including surgery, radio‑ were performed to investigate the synergy between G47Δ and therapy and chemotherapy, can successfully cure patients TMZ in regulating breast cancer cell behavior in vitro. The or prolong patient survival in the majority of cases, each of role of G47Δ and TMZ in suppressing tumorigenesis in vivo these therapies has limitations, such as the inability of surgery was investigated in a xenograft mouse model. G47Δ and TMZ to eliminate distant metastasis, the lack of durable response served a synergistic role resulting in decreased breast cancer to radiotherapy and drug resistance to chemotherapy (2). cell viability, induction of cell cycle arrest, promotion of tumor Therefore, there is an urgent need to develop new effective cell apoptosis and enhancement of DNA damage response therapeutic approaches for breast cancer treatment. in vitro. The combined administration of G47Δ and TMZ Oncolytic viruses can selectively infect, replicate in, and also effectively suppressed breast cancer cell‑derived tumor kill cancer cells via induction of cancer cell lysis and the host growth in vivo, compared with the administration of G47Δ or immune response in infected cancer cells, which results from cancer antigen exposure in lysed cancer cells (3). Notably, onco‑ lytic viruses do not harm healthy cells. Oncolytic virus‑based therapy has been regarded as a potential novel therapeutic strategy for cancer treatment (4). Oncolytic viruses have been Correspondence to: Dr Renbin Liu, Breast Cancer Center, genetically engineered to improve both the safety of treatment Department of Breast and Thyroid Surgery, The Third Affiliated and selectivity (5). Talimogene laherparepvec, a genetically Hospital of Sun Yat‑sen University, 600 Tianhe Road, Guangzhou, modified herpes simplex virus (HSV), has been approved by Guangdong 510630, P.R. China the US Food and Drug Administration for clinical application E‑mail: [email protected] in advanced melanoma therapy (6). Oncolytic HSV G47Δ is a Mr. Binlin Ma, Department of Breast and Neck Surgery, Xinjiang third‑generation replication‑competent HSV‑1 vector derived Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang from G207 with the deletion of the infected cell protein 47 830011, P.R. China (ICP47) gene and both copies of the γ34.5 gene (7). G47Δ has E‑mail: [email protected] been used to treat glioblastoma in clinical trials in Japan (7). *Contributed equally Temozolomide (TMZ) is an imidazotetrazine‑derived alkylating agent used as a first‑line oral drug for the treat‑ Abbreviations: TMZ, temozolomide; HSV, herpes simplex virus; ment of malignant glioma because it is able to easily pass MOI, multiplicity of infection; CI, combination index through the blood‑brain barrier due to its low molecular weight and lipophilicity (8,9). In addition, TMZ has been Key words: breast cancer, oncolytic HSV, TMZ, synergy used in clinical trials for the treatment of advanced metastatic melanoma (10,11). TMZ kills cancer cells via induction of DNA alkylation and methylation damage in cancer cells (12). 2 FAN et al: G47Δ AND TMZ IN BREAST CANCER THERAPY However, certain types of cancer cells are able to repair was removed carefully, and DMSO was added to dissolve the TMZ‑induced DNA damage, leading to resistance to TMZ, blue formazan crystals. The optical density was measured at while the genetically modified oncolytic HSV has a decreased 490 nm. replication efficacy in cancer cells compared with naturally occurring HSV, which both decreased the anti‑cancer efficacy Chou‑Talalay analysis of drug synergy. Chou‑Talalay of such therapies (13,14). Since the therapeutic targets of TMZ analysis (17,18) was performed to determine the combina‑ and HSV are different, a strategy using a combination of TMZ tion index (CI) via assessment of the cell growth inhibition and HSV may notably enhance the efficacy of cancer therapy in G47Δ and/or TMZ‑treated tumor cells using the following via a complementary mechanism. equation: CI=(D)1/(Dx)1 + (D)2/(Dx)2, where (Dx)1 is the dose The present study investigated the combined role of TMZ of agent 1 (e.g. G47Δ) required to produce x percentage effect and G47Δ in regulating breast cancer cell behavior in vitro and alone and (D)1 is the dose of agent 1 required to produce the in vivo, and a preliminary mechanism was also suggested. The same x percentage effect in combination with (D)2. Similarly, results of the present study may provide valuable insight into (Dx)2 is the dose of agent 2 (e.g. TMZ) required to produce the development of novel therapeutic approaches to treat breast x percentage effect alone and (D)2 is the dose required to cancer. produce the same effect in combination with (D)1. The denominators of the aforementioned CI equation, (Dx)1 and 1/m Materials and methods (Dx)2, can be determined by Dx=Dm[fa/(1‑fa)] , where Dm is the dose required for a 50% effect (e.g. 50% inhibition of cell Cell lines and culture. The human breast cancer cell lines growth), fa is the fraction affected by D (e.g. 0.5 if cell growth SK‑BR‑3 and MDA‑MB‑468, as well as the African green is inhibited by 50%), and m is the coefficient of sigmoidicity of monkey kidney epithelial cell line Vero, were gifts from the dose‑effect curve. Different values of CI may be obtained Dr. Musheng Zeng (Sun Yat‑sen University Cancer Center, to solve the equation for different values of fa (e.g. different Guangzhou, China). These cells were grown in Dulbecco's degrees of inhibition of cell growth). CI<1 indicates synergy, modified Eagle's medium (DMEM; Gibco; Thermo Fisher CI>1 indicates antagonism and CI=1 indicates an additive Scientific, Inc.) supplemented with 10% inactivated fetal calf effect. EnzFitter software, version 1.22 (Biosoft) was used to serum (FCS; Gibco; Thermo Fisher Scientific, Inc.), 100 IU/ml determine the CI values. penicillin, 100 µg/ml streptomycin and 2 mM L‑glutamine. All cells were maintained in a humidified incubator with 5% Flow cytometry. A preliminary experiment was performed CO2 at 37˚C. using SK‑BR3 and MDA‑MB468 cells after treated with a single drug for 48 h to determine the IC50. Subsequently, Amplification of G47Δ. G47Δ was a gift from Dr. Samuel D. these drug doses were used to assess the effects on tumor Rabkin (Harvard Medical School, Boston, MA, USA) and apoptosis. In brief, the cells were seeded into a 6‑well plate diluted in 1% inactivated FCS‑containing PBS to infect Vero at a density of 3x105 cells/well and cultured at 37˚C for 24 h. cells at a multiplicity of infection (MOI) of 0.03, followed by The cells were then treated with 2 µl DMSO (control), G47Δ incubation under standard conditions (5% CO2 and 37˚C) for (MOI, 0.01), and/or TMZ (6 µM for SK‑BR‑3 and 60 µM for 90 min. Viral inoculums were then removed and replaced MDA‑MB‑468) in DMEM containing 1% FCS for 48 h or with 3% inactivated FCS‑containing DMEM, followed by 72 h. For the cell cycle analysis, the cells were cultured for incubation in 5% CO2 for 48‑72 h at 34.5˚C. Infected cells 72 h and then collected, washed with PBS three times and were collected when >90% of the cells appeared round and resuspended, followed by overnight fixation in 70% ethanol refractile under a light microscope (magnification, x400) after at 4˚C. On the next day, the cells were incubated with RNase calculation of 200 cells with two or more fused nuclei vs. A at 37˚C for 1 h and then stained with 1 µg/ml propidium the total nuclei (fused and un‑fused nuclei) by two investiga‑ iodide (PI) in the dark at 4˚C for 30 min. Fluorescence of the tors and then resuspended in the virus buffer (20 mM Tris stained cells was detected for cell cycle analysis via the flow and 150 mM NaCl; pH 7.5). The resuspension solution was cytometer FACSCanto II (BD Biosciences).
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