Newcastle disease virus enhances the antitumor efficacy of Doxorubicin in a cervical cancer mouse model.

BACKGROUND AND AIMS: Cervical cancer (CC) is a common cancer among women, often treated with Doxorubicin (Doxo). Research is underway to explore the use of oncolytic virus (OV) therapy as a means to improve drug efficacy and enhance the immune system's tumor-fighting capabilities. Hence, our study purposes to evaluate the therapeutic potential of Newcastle disease virus (NDV) in increasing the antitumor efficacy of Doxo in mouse models of CC. METHODS AND MATERIALS: TC1 cells were administered to C57BL/6 mice (Female) in a range of 6 to 8 weeks age (n = 40) to induce tumor growth. After tumor development, four treatment groups of mice were formed. Treatment were performed through NDV, Doxo, and a combination of both in three groups of treatment twice in a one-week intervention manner, while the control group treated with PBS. Following the last treatment, half of these mice were subjected to euthanize due to the immune-response assessment, and the other half were followed up till they died naturally in a certain period of time. RESULTS: Mice that underwent the combined treatment showed significantly improved survival rates and slower tumor progression in comparison with the control group. This combined treatment substantially elevated nitric oxide (NO) and lactate dehydrogenase (LDH) levels in the splenocytes cultures of mice bearing cervical tumors. Furthermore, combination therapy resulted in a notable elevation in TNF-α, IL-12, and IFN-γ, secretion alongside a reduction in the release of TGF-ß and IL-4 within the splenocytes in counter with the treatment of just NDV or Doxo. CONCLUSION: According to the findings of this study, it seems that utilizing NDV can improve the effectiveness of Doxo in a mouse model of CC, suggesting it can serve as an adjunct therapy alongside chemotherapy.

Vitamin D3 (Calcitriol) Monotherapy Decreases Tumor Growth, Increases Survival, and Correlates with Low Neutrophil-to-Lymphocyte Ratio in a Murine HPV-16-Related Cancer Model.

Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy with cisplatin (CP) reduces tumor growth and affects survival and systemic inflammation. Treatments were administered to C57BL/6 mice with HPV-16-related tumors (TC-1 cells) as follows: (1) placebo (100 µL vehicle, olive oil, orally administered daily); (2) VitD3 (3.75 µg/kg calcitriol orally administered daily); (3) CP (5 mg/kg intraperitoneally, every 7 days); and (4) VitD3+CP. Tumor growth was monitored for 25 days, survival for 60 days, and the neutrophil-to-lymphocyte ratio (NLR) was evaluated on days 1 (baseline), 7, and 14. VitD3+CP showed greater success in reducing tumor volume compared to CP monotherapy (p = 0.041), while no differences were observed between CP and VitD3 monotherapy (p = 0.671). Furthermore, VitD3+CP prolonged survival compared to CP (p = 0.036) and VitD3 (p = 0.007). Additionally, at day 14 the VitD3 and VitD3+CP groups showed significantly lower NLR values than the CP group (p < 0.05, for both comparisons). Vitamin D3 could be a promising adjuvant in the treatment of cervical cancer or solid tumors and deserves further investigation.

Anti-tumor Effects of Cisplatin Synergist in Combined Treatment with Clostridium novyi-NT Spores Against Hypoxic Microenvironments in a Mouse Model of Cervical Cancer Caused by TC-1 Cell Line.

Purpose: Despite the development of anti-human papillomavirus (HPV) vaccines, cervical cancer is still a common disease in women, especially in developing countries. The presence of a hypoxic microenvironment causes traditional treatments to fail. In this study, we presented a combined treatment method based on the chemotherapeutic agent cisplatin and Clostridium novyi-NT spores to treat normoxic and hypoxic areas of the tumor. Methods: TC-1 Cell line capable of expressing HPV-16 E6/7 oncoproteins was subcutaneously transplanted into female 6-8 week old C57/BL6 mice. The tumor-bearing mice were randomly divided into four groups and treated with different methods after selecting a control group. Group 1: Control without treatment (0.1 mL sterile PBS intratumorally), Group: C. novyi-NT (107 C. novyi-NT). Group 3: Receives cisplatin intraperitoneally (10 mg/kg). Fourth group: Intratumoral administration of C. novyi-NT spores + intraperitoneal cisplatin. Western blot analysis was used to examine the effects of anti-hypoxia treatment and expression of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) proteins. Results: The results clearly showed that combined treatment based on C. novyi-NT and cisplatin significantly reduced the expression of HIF-1 alpha and VEGF proteins compared to cisplatin alone. At the same time, the amount of necrosis of tumor cells in the combined treatment increased significantly compared to the single treatment and the control. At the same time, the mitotic count decreased significantly. Conclusion: Our research showed that developing a combined treatment method based on C. novyi-NT and cisplatin against HPV-positive cervical cancer could overcome the treatment limitations caused by the existence of hypoxic areas of the tumor.

Combined extract of heated TC1, a heat-killed preparation of Lactobacillus casei and alpha-galactosyl ceramide in a mouse model of cervical cancer.

BACKGROUND: Nowadays, cancer is the leading cause of death among threats to humanity, necessitating prompt action and preparation. Cervical cancer is one of the most common cancers in women and is currently treated with surgery, radiation, chemotherapy, and immunotherapy, among other treatments. Current oncology approaches focused on the simultaneous development of safe and effective cancer multi-agent therapies. The present study aimed to evaluate the effects of a combined extracts of heated TC1, a heat-killed preparation of Lactobacillus casei, and alpha-galactosyl ceramide (α-GalCer) in a mouse model of cervical cancer. MATERIAL AND METHODS: Cervical cancer in the mouse model was prepared by TC1 cells subcutaneous injection into the left flank of female C57BL/6 mouse aged 6-8 weeks (n = 80). After the appearance of the palpable tumor, the mice with cervical cancer were randomly devoted to 8 (ten-member) groups. The mice in some groups were treated with PBS, TC1 cell extract, L. casei extract, α-GalCer, and a combination of the mentioned treatments. Then, they were evaluated the splenocytes proliferation, lactate dehydrogenase production and nitric oxide. Moreover, IL-4, IFN-γ, and TGF-ß cytokine levels of splenocytes supernatant the mice were measured. In all evaluations, a statistical difference of less than 0.05 (P ˂ 0.05) was considered as a significant level. RESULT: The findings revealed that the combination therapy group (heated TC1 cell and L. casei extracts with α-GalCer) significantly increases the splenocytes proliferation (MTT) (0.358 ± 0.04 OD), LDH production (45.9 ± 2.3 U/L), NO rate (38.4 ± 2.8 µM), and IFN-γ cytokine level (46.6 ± 3.7 pg/ml) (P < 0.05). Also, observes a significantly reduces the production of IL-4 (11.6 ± 2.5 pg/ml) and TGF-ß cytokines levels (7.8 ± 2.5 pg/ml) (P < 0.05) in comparison to the control group. CONCLUSION: The study showed that combination therapy of L. casei and α-GalCer is an efficient treatment for cervical cancer in the mouse model.

Mesenchymal stem cells support delivery and boost the efficacy of oncolytic reoviruses in TC-1 tumor cells.

Cancer has remained a major health problem around the world. Mesenchymal stem cells (MSCs)-based therapy exhibits a therapeutic effect via different mechanisms. By using MSCs as carrier cells, the major problem of clearance of oncolytic viruses is resolved by neutralizing antibodies before they react with cancer cells. The aim of this study was to characterize the effect of infected MSCs by reovirus type-3 Dearing (T3D) for in vitro cancer therapy. Adipose-derived MSCs (AD-MSCs) were infected with reovirus T3D and its biological properties were evaluated. Then, the effects of reovirus-infected AD-MSCs on cytokine profile, nitric oxide (NO) production, and apoptosis induction in TC-1 cells were assessed. Our results indicated that the differentiation potential of AD-MSCs was affected by reovirus. However, phenotypes were not affected after infection. Then, the effects of reovirus-infected AD-MSCs in TC-1 cells showed an increased amount of tumor necrosis factor-alpha (TNF-α) and NO production and a decreased amount of transforming growth factor-beta 1 (TGF-ß1) and interleukin-10 (IL-10). Moreover, apoptosis significantly increased via coculturing of TC-1 cells with infected AD-MSCs, compared with control, and both internal and external apoptosis pathways are activated in experimental groups. In conclusion, the data showed that with increasing TNF-α and NO production and reducing IL-10 and TGF-ß production, AD-MSCs can enhance the oncolytic effect of reovirus in cancer cells. Furthermore, the results suggested that AD-MSCs can be used as effective carrier cells candidate for reovirus T3D to maximize their anticancer cell activity.

Immune modulation of a lipid-soluble extract of Pinellia pedatisecta Schott in the tumor microenvironment of an HPV+ tumor-burdened mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Pinellia pedatisecta Schott extract (PE), a traditional Chinese medicine, has been used to reduce swelling, dry dampness and suppress cervical tumors. AIMS: To evaluate the roles of PE in the regulation of anti-tumor effects and the cellular immune response in the tumor microenvironment. METHODS: The immune microenvironment of HPV+TC-1 tumors was examined by immunohistochemistry, real-time PCR and flow cytometry. RESULTS: Our study demonstrated that PE in vitro could significantly increase the percentage of apoptosis and necrosis in HPV+TC-1 cells and block the cell cycle phase. In vivo treatment with PE eradicated established subcutaneous HPV+TC-1 tumors in wild-type C57BL/6 mice by infiltrating CD8+ T cells and CD4+ T cells and by directly suppressing tumor growth and resistance to avascular necrosis. The key factors in the canonical Wnt signaling pathway in the experimental group (PE+mDC+naive CD4+T cells) were challenged, and the levels of beta-catenin, C-myc, cyclin D1 and PPAR1 were significantly enhanced at the 5th day. In particular, the subset proportion of Th1 cells (characterized by IFNγ production and the transcription factor Tbet) increased significantly, and both Th2 cells (characterized by IL-4 production and the transcription factor GATA3) and Th17 cells (characterized by IL-17 production and the transcription factor RoRγt) decreased profoundly. CONCLUSIONS: These findings linked the anti-tumor properties of PE with the immune microenvironment to present a reliable basis for the future practical application of PE in cervical cancer as a novel and pharmacologically safe immunotherapy strategy.