scholarly journals CD73 Downregulation by EGFR-Targeted Liposomal CD73 siRNA Potentiates Antitumor Effect of Liposomal Doxorubicin (Doxil) in 4T1 Tumor-Bearing Mice  

2021 ◽  
Author(s):  
Anvar Soleimani ◽  
Farshad Mirzavi ◽  
Sara Nikoofal sahlabadi ◽  
Amin reza Nikpoor ◽  
Bita Taghizadeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Mouse Model ◽  
Mtt Assay ◽  
Antitumor Effect ◽  
Control Group ◽  
Liposomal Formulations ◽  
P 16 ◽  
Cd73 Downregulation

Abstract Background Blocking CD73 ectonucleotidase has been proposed as a potential therapeutic approach for cancer treatment. The purpose of the present study was to investigate the antitumor effect of a novel EGFR-Targeted liposomal CD73 siRNA formulation in combination therapy with Doxil in the 4T1 mouse model. Methods CD73 siRNA was encapsulated into nanoliposomes by the ethanol injection method. After preparation, characterization, morphology, and stability evaluation of formulations, the toxicity was measured by MTT assay. Uptake assay and efficiency of the liposomal formulations were investigated on the 4T1 cell line. The liposomal formulation containing CD73 siRNA was targeted with GE11 peptide for in vivo evaluations. Antitumor activity of prepared formulations in combination with Doxil was studied in mice bearing 4T1 metastatic breast cancer cells. Finally, the antitumor efficacy of the formulation in concomitant treatment with Doxil was evaluated in a mouse model of breast cancer. Results The size of prepared liposomal formulations at N/P=16 for the liposomal CD73 siRNA and GE11-lipo CD73 siRNA groups were 89 nm ± 4.4 and 95 nm ± 6.6, respectively. The nanoparticle’s PDI was less than 0.3 and their surface charge was below 10 mV. The results demonstrated that N/P=16 yielded the best encapsulation efficiency which was 94% ± 3. 3. AFM results showed that the liposomes were spherical in shape and were less than 100 nm in size. The results of the MTT assay showed significant toxicity of the liposomes containing CD73 siRNA during the 48-hour cell culture. Real-time PCR and flow cytometry results showed that liposomes containing CD73 siRNA could effectively downregulate CD73 expression. Liposomal formulations were able to significantly downregulate CD73 gene expression, in vivo. However, CD73 downregulation efficiency was significantly higher for targeted form in comparison with non-targeted formulation (P-value <0.01). The combination showed maximum tumor growth delay with remarkable survival improvement compared to the control group. Studying the immune responses in the treatment groups which received doxorubicin, showed decreased number of lymphocytes in the tumor environment. However, this decrease was lower in the combination therapy group. Finally, our results clearly showed that CD73 downregulation increases the activity of CD8+ lymphocytes (INF-ℽ production) and also significantly decreases the Foxp3 in the CD25+ lymphocytes compared to the control group. Conclusion GE11-Lipo CD73 siRNA formulation can efficiently knock down CD73 ectonucleotidase. Also, the efficacy of Doxil is significantly enhanced via the downregulation of CD73 ectonucleotidase.

scholarly journals Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer

2012 ◽  
Vol 58 (3) ◽  
pp. 326-338
Author(s):  
E.V. Moiseeva ◽  
N.R. Kuznetsova ◽  
E.V. Svirshchevskaya ◽  
N.V. Bovin ◽  
N.S. Sitnikov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Sialyl Lewis X ◽  
Antimitotic Agent ◽  
Combretastatin A4 ◽  
Mouse Breast Cancer

The antimitotic agent combretastatin A4 (СА-4) has been suggested as an antivascular agent for anticancer therapy relatively recently. To reduce systemic toxicity by means of administration in liposome formulations, in this study new lipophilic prodrugs, oleic derivatives of СА-4 and its 4-arylcoumarin analog (СА4-Ole and ArC-Ole, respectively), have been synthesized: Liposomes of 100 nm mean diameter prepared on the basis of egg phosphatidylcholine and phosphatidylinositol from bakers yeast have been shown to include completely up to 10 mol. % of СА4-Ole, or 7 mol. % of ArC-Ole. Also, prodrug bearing liposomes decorated with tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been constructed to achieve targeting to endothelium under neovascularization. The antitumor activity in vivo was studied in the model of slowly growing mouse breast cancer. Under the used dose (22 mg/kg) as well as the regimen of treatment (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect, and oppositely even stimulated tumor growth. Liposome formulations of CA4-Ole did not show such stimulation. However, to achieve pronounced antitumor effect, number of injections of liposomes should be apparently elevated. New antimitotic agent ArC revealed cytotoxic activity of only one tenth value obtained for CA-4 in vitro in the culture of human breast carcinoma cells. Nevertheless, in vivo in the mouse model of breast cancer this compound showed antitumor effect under double СА-4 equivalent dose. The results demonstrate availability of SiaLeX-liposomes loaded with ArC-Ole: this preparation began to inhibit tumor growth already after the second injection. It is necessary further to choose doses and regimens of administration both for ArC and liposome formulations bearing ArC-Ole.

scholarly journals Naringenin and Metformin Enhance the Antitumor Effect of Doxorubicin Against Experimental Models of Breast Carcinoma

2021 ◽  
Author(s):  
Bharat Pateliya ◽  
Vinod Burade ◽  
Sunita Goswami
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Breast Carcinoma ◽  
Antitumor Activity ◽  
Mouse Model ◽  
Combination Treatment ◽  
Survival Data ◽  
Antitumor Effect ◽  
Tumor Weight

Abstract Breast cancer is the most common malignancy in women worldwide and is curable in patients at an early stage. The present work is aimed to evaluate the potential of naringenin and metformin concomitant addition with doxorubicin chemotherapy against experimental breast carcinoma models. The antitumor potential of drugs under the study was evaluated in vivo against methylnitrosourea (MNU)- induced breast cancer in rats and 4T1- induced orthotropic mouse model. Tumor-bearing animals were randomly divided into various groups to assess the effect of each single drug and concomitant drug treatments. Parameters like tumor growth, body weight, survival rate, blood glucose, hematology and histology study were determined. There was significant reduction in tumor weight and an observed decrease in tumor multiplicity in naringenin and metformin concomitant addition with doxorubicin treatment as compared to doxorubicin alone against MNU-induced breast carcinoma. Likewise, significant reduction of tumor volume and tumor weight was also observed in 4T1 mouse model suggesting combination treatment enhanced antitumor activity in vivo. Further, histology of tumor biopsies presented enhanced antitumor activity of doxorubicin through increasing tumor necrosis. Hematological parameters, body weight and survival data presented better safety of combination treatment without compromising efficacy using lower dose of doxorubicin as compared to large dose of doxorubicin alone. These results demonstrate that naringenin and metformin enhanced the antitumor effect of doxorubicin in animal models of breast carcinoma and useful as an adjunct to increase the effectiveness of doxorubicin at lower dose.

scholarly journals Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

2021 ◽  
Vol 14 (3) ◽  
pp. 254
Author(s):  
Afnan H. El-Gowily ◽  
Samah A. Loutfy ◽  
Ehab M. M. Ali ◽  
Tarek M. Mohamed ◽  
Mohammed A. Mansour
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mtor Pathway ◽  
Tumor Growth Inhibition ◽  
Autophagic Flux ◽  
Ki 67 ◽  
Mcf 7

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

scholarly journals Antiproliferation Effects of Nanophytosome-Loaded Phenolic Compounds From Fruit of Juniperus Polycarpos Against Breast Cancer in Mice Model: Synthesis, Characterization and Therapeutic Effects

2021 ◽  
Author(s):  
Soheila Moeini ◽  
Ehsan Karimi ◽  
Ehsan Oskoueian
Keyword(s):  
Breast Cancer ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Therapeutic Effects ◽  
Mice Model ◽  
Fruit Extract ◽  
Phenolic Fraction ◽  
Juniperus Polycarpos

Abstract Background: This research was performed to synthesize nanophytosomes-loaded high phenolic fraction (HPF) from Juniperus polycarpos fruit extract and investigate its antiproliferation effects against breast cancer in mice model. Results: The nanophytosomes-loaded HPF from Juniperus polycarpos fruit extract was synthesized. The mice trial was conducted to determine the possible toxic effects of the synthesized nanophytosomes. The anticancer, pro-apoptotic, and antioxidative activities of the nanophytosomes were determined. The nanophytosomes-loaded HPF had a spherical structure with a size of 176 nm and a polydispersity index coefficient of 0.24. The in-vivo study manifested that nanophytosomes-loaded HPF significantly improved weight gain and food intake compared to the negative control group (p<0.05). The nanophytosomes-loaded HPF significantly enhanced the expression of bax (3.4-fold) and caspase-3 (2.7-fold) genes but reduced bcl2 (3.6-fold) gene expression in tumor cells. The average tumor size was significantly decreased in mice treated with nanophytosomes-loaded HPF (p<0.05). The expression of GPX (2.3-fold) and SOD (2.7-fold) antioxidants in the liver of mice supplemented with nanophytosomes-loaded HPF was significantly developed compared to the negative control (p<0.05). The nanophytosomes-loaded HPF did not show toxicity on normal cells. Conclusion: Our results indicated that nanophytosomes-loaded HPF might be a potential anticancer agent for the breast cancer treatment.

Anlotinib enhanced penpulimab efficacy through remodeling of tumor vascular architecture and immune microenvironment in hPD-L1/hPD-1 humanized mouse model.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2581-2581
Author(s):  
Yunlong Shan ◽  
Chongjin Zhong ◽  
Qi Ni ◽  
Mengying Zhang ◽  
Guangji Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Mouse Model ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumor Volume ◽  
Combined Therapy ◽  
Control Group ◽  
Tyrosine Kinase Receptor ◽  
Humanized Mouse ◽  
Humanized Mouse Model

2581 Background: Even though immune checkpoint inhibitor (ICI) such as anti-PD-1 mAb has emerged as effective treatment for tumor regression, the response rate of ICI monotherapy in solid tumor is low. Many studies have demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. Penpulimab (AK105), a humanized IgG1 mAb that blocks PD-1 binding to PD-L1, engineered to eliminate FcγR binding and ADCC/ADCP completely. Here, we explore a new combined therapy of penpulimab and anlotinib, an oral multi-targeted tyrosine kinase receptor inhibitor. Methods: MC38-hPD-L1 tumor-bearing B-hPD-1 humanized mouse model were conducted to investigate the effects of anlotinib (1 mg/kg, every day, p.o) or penpulimab (5 mg/kg, twice a week, i.p) alone or in combination. Immunofluorescence was applied to elucidate tumor vessel normalization. In vivo imaging was conducted to detect the distribution of AF647-labelled penpulimab after anlotinib treatment. Flow cytometry and other techniques were performed to investigate intratumoral immune cells. Results: After 3-week treatment, immunotherapeutic administration of anlotinib or penpulimab showed moderate inhibition of tumor growth (tumor volume: 66.5% and 58.4% of control group, respectively), while combined treatment of anlotinib with penpulimab significantly decreased tumor volume to 36.5% of control group. Tissue pathological and blood biochemical results showed no significant toxic and side effects. Immunohistochemistry revealed that anlotinib induced tumor vascular normalization, indicated by decreased CD31+ area, increased α-SMA around tumor vessels and reduced GLUT1+ area. Furthermore, anlotinib markedly enhanced the delivery of AF647-penpulimab into tumors. Combining anlotinib with penpulimab also promoted infiltration and activity of anti-tumoral immune cells by reducing the level of immune checkpoint TIM3 and increasing the IFNγ secretion from T cells. Conclusions: Our work provides a strong scientific rationale for the combination therapy of anlotinib and penpulimab to improve tumor microenvironment and immunotherapy, which highlights the clinical potential for this new combined therapy.

scholarly journals Taurine Attenuates Carcinogenicity in Ulcerative Colitis-Colorectal Cancer Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Guifeng Wang ◽  
Ning Ma ◽  
Feng He ◽  
Shosuke Kawanishi ◽  
Hatasu Kobayashi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drinking Water ◽  
Mouse Model ◽  
Histopathological Examination ◽  
Tumor Formation ◽  
Water Model ◽  
Control Group ◽  
Ki 67

Taurine (2-aminoethane-sulfonic acid) is a type of amino acids and has numerous physiological and therapeutic functions, including anti-inflammation. However, there are few studies on the anticancer action of taurine. Our previous studies have demonstrated that taurine exhibits an apoptosis-inducing effect on human nasopharyngeal carcinoma cells in vitro. In this study, we have investigated whether taurine has an anticancer effect, using azoxymethane (AOM)/sulfate sodium (DSS)- induced mouse model for colon carcinogenesis. All mice, except those in control group, received a single intraperitoneal injection of AOM and DSS in the drinking water for 7 days twice, with 1-week interval. After the first DSS treatment, mice were given distilled water (model group) or taurine in the drinking water (taurine group) ad libitum. No tumor was observed in the control group. Taurine significantly suppressed AOM+DSS-induced tumor formation. Histopathological examination revealed AOM/DSS treatment induced colon cancer in all mice (8/8, 100%), and taurine significantly inhibited the progression of colon cancer (4/9, 44.4%). Taurine significantly attenuated cell proliferation in cancer tissues detected by Ki-67 staining. Taurine significantly increased the levels of an apoptosis marker cleaved caspase-9 and tumor suppressor protein PTEN. This is the first study that demonstrated that taurine significantly reduced carcinogenicity in vivo using AOM/DSS-induced colon cancer mouse model.

scholarly journals The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Brianna M. Craver ◽  
Thanh Kim Nguyen ◽  
Jenny Nguyen ◽  
Hellen Nguyen ◽  
Christy Huynh ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Mouse Model ◽  
Characteristic Feature ◽  
Kinase Activity ◽  
Differential Sensitivity ◽  
Smac Mimetics ◽  
Smac Mimetic ◽  
Mutant Cells

Abstract Background Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2V617F–driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2V617F–driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results We found that JAK2V617F-mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is required for JAK2V617F-mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2V617F-driven MPN. Conclusion LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN.

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