scholarly journals Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 547
Author(s):  
Mariangela Garofalo ◽  
Laura Bertinato ◽  
Monika Staniszewska ◽  
Magdalena Wieczorek ◽  
Stefano Salmaso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enzyme Assay ◽  
Survival Rates ◽  
Oncolytic Adenovirus ◽  
The Novel ◽  
Anti Cancer ◽  
Check Point Inhibitors ◽  
Melanoma Therapy

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

scholarly journals Berberine inhibits the proliferation of pancreatic cancer targeting pancreatic cancer stem cells

2021 ◽  
Author(s):  
Mengmeng Liu ◽  
Yue Pan ◽  
Xufeng Tao ◽  
Ning Li ◽  
Kun Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Effectiveness ◽  
The Novel ◽  
Migration Assay ◽  
Medicinal Value ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Pancreatic Cancer Stem Cells

Abstract BackgroundPDAC is universally acknowledged to be one of the highest mortality rate of cancer-related deaths. PCSCs, regulated by EMT, could promote the proliferation of PDAC. Berberine with high medicinal value has usually been used as an anti-cancer agent. Hence the purpose of this study is to investigate the anti-cancer effect of berberine in PDAC. MethodsMTT assay was used to verify berberine inhibiting the proliferation of PDAC. Immunofluorescence staining, stem cell sphere, wound healing and transwell migration assay were demonstrated the anti-proliferation and anti-stemness of PCSCs in vitro . PANC-02 cells were injected in C57BL/6 mice to establish the orthotopic pancreatic-cancer model in vivo . H&E and Ki67 immunohistogical staining assay were used to evaluated the effect of berberine in PDAC in vivo. q-PCR and Western blot methods were applied to detect the expression of EMT procedure.ResultsIn this study, berberine has selective anti-cancer effect in PDAC in vitro . Moreover, berberine suppressed the proliferation and stemness of PCSCs in PDAC. In vivo , berberine reduced the tumor size and decreased the expression of Ki67 in orthotopic pancreatic-cancer pancreases. In addition, berberine inhibit the EMT signaling pathway both in vitro and in vivo . ConclusionsOur study indicates that berberine inhibit the proliferation of PDAC in vivo and vitro . The mechanism of anti-cancer effect on berberine may suppress the PCSCs through inhibiting EMT procedure. Therefore, berberine may be the novel antineoplastic drug with clinical effectiveness in PDAC. Keywords: Berberine, PDAC, PCSCs, EMT, berberine

scholarly journals Two-stage nanoparticle delivery of piperlongumine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) anti-cancer therapy

TECHNOLOGY ◽  
2016 ◽  
Vol 04 (01) ◽  
pp. 60-69 ◽  
Author(s):  
Charles C. Sharkey ◽  
Jiahe Li ◽  
Sweta Roy ◽  
Qianhui Wu ◽  
Michael R. King
Keyword(s):  
Cancer Cells ◽  
Survival Rates ◽  
Xenograft Model ◽  
Plga Nanoparticles ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
In Vivo Testing ◽  
Hct116 Cells

This study outlines a drug delivery mechanism that utilizes two independent vehicles, allowing for delivery of chemically and physically distinct agents. The mechanism was utilized to deliver a new anti-cancer combination therapy consisting of piperlongumine (PL) and TRAIL to treat PC3 prostate cancer and HCT116 colon cancer cells. PL, a small-molecule hydrophobic drug, was encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles. TRAIL was chemically conjugated to the surface of liposomes. PL was first administered to sensitize cancer cells to the effects of TRAIL. PC3 and HCT116 cells had lower survival rates in vitro after receiving the dual nanoparticle therapy compared to each agent individually. In vivo testing involved a subcutaneous mouse xenograft model using NOD-SCID gamma mice and HCT116 cells. Two treatment cycles were administered over 48 hours. Higher apoptotic rates were observed for HCT116 tumor cells that received the dual nanoparticle therapy compared to individual stages of the nanoparticle therapy alone.

Effect of AdipoR agonist in cholangiocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 323-323
Author(s):  
Khac Cuong Bui ◽  
Mai Ly Thi Nguyen ◽  
Samarpita Barat ◽  
Xi Chen ◽  
Vikas Bhuria ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Cell Lines ◽  
Colony Formation ◽  
Tumor Burden ◽  
Potential Candidate ◽  
Anti Cancer ◽  
Apoptosis Assay

323 Background: Adiponectin is the key adipokine, which plays an important role in health and disease such as obesity, diabetes, and cancer. Adiponectin is reduced in different tumor types, especially in obesity-related cancer, and recent studies showed that Adiponectin had a potential anti-cancer effect. Obesity is a risk factor for various tumor diseases including cholangiocarcinoma (CC), the second most common primary hepatic cancer. The aim of this study is to investigate for the first time the anti-cancer effect of AdipoR agonist in CC cell lines and a CC engineered mouse model. Methods: Human CC cell lines (TFK-1 and SZ-1) and CC engineered mice (Alb-Cre/KRASG12D/p53L/L) were used to investigate the anti-cancer effects of an AdipoR agonist (2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide). Cell proliferation, migration, invasion, colony formation, apoptosis assay were applied to evaluate the effect of AdipoR agonist in vitro. In addition, important cancer signalling pathways and targets were analysed by Western Blot. Mice (n = 12) were treated with AdipoR or verhicle and tumor burden and survival were monitored. Results: AdipoR agonist suppressed proliferation, migration, invasion, colony formation and apoptosis in CC cells. AdipoR agonist regulated the expression of different proteins such as EMT markers, pAMPK, pSTAT3, and PARP, which have pivotal functions in cholangiocarcinogenesis. AdipoR agonist also prolonged survival time in a CC engineered mouse model. Conclusions: Our data revealed that AdipoR agonist inhibited successfully cell proliferation, migration, invasion, colony formation and apoptosis in vitro, and prolonged mice survival in vivo through regulation of crucial signaling pathways in cholangiocarcinogenesis. These results suggested that AdipoR agonist might become a new potential candidate for CC treatment in the future.

scholarly journals Antibiotic Treatment of Experimental Pneumonic Plague in Mice

1998 ◽  
Vol 42 (3) ◽  
pp. 675-681 ◽  
Author(s):  
William R. Byrne ◽  
Susan L. Welkos ◽  
M. Louise Pitt ◽  
Kelly J. Davis ◽  
Ralf P. Brueckner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Antibiotic Treatment ◽  
Survival Rates ◽  
Blood Cultures ◽  
High Dose ◽  
Beta Lactam ◽  
Pneumonic Plague ◽  
Beta Lactam Antibiotics

ABSTRACT A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized Yersinia pestisorganisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia.

scholarly journals Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 49 ◽  
Author(s):  
Young Yun Jung ◽  
Muthu K. Shanmugam ◽  
Acharan S. Narula ◽  
Chulwon Kim ◽  
Jong Hyun Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Mouse Model ◽  
A549 Cells ◽  
Xenograft Model ◽  
Signaling Cascade ◽  
Anticancer Effects ◽  
Anti Cancer

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo.

Combination Therapy of Humanized Chimeric-Anti-Human VLA4 Monoclonal Antibodies and Anti-Cancer Drugs for AML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4518-4518
Author(s):  
Takuya Matsunaga ◽  
Kazunori Kato ◽  
Maki Tanaka ◽  
Yukari Masuta ◽  
Kageaki Kuribayashi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Scid Mouse ◽  
Variable Region ◽  
Human Leukemia ◽  
Region Gene ◽  
Anti Cancer ◽  
Variable Region Gene ◽  
Scid Mouse Model

Abstract Bone marrow (BM) minimal residual disease causes relapse after chemotherapy in AML. We have previously reported that VLA4-positive leukemic cells acquired resistance to drug-induced apoptosis through the PI-3K/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA4 and fibronectin on BM stromal cells. This resistance was negated by mouse-anti-human VLA4Ab (mouse VLA4Ab). In human leukemia SCID mouse model, we demonstrated a 100% survival rate with combination of mouse VLA4 Ab and AraC, while with AraC alone, only slight prolongation of survival was attained. In clinical study, overall survival at 5 years was 90% for 10 VLA4− patients and 25% for 15 VLA4+ patients (Matsunaga T et al, Nature Med 2003, 9, 1158–1165). In the present study, to perform the translational research, we first examined the myelosuppressive effect of the combination of rat-anti-mouse VLA4 Ab and AraC in C57/BL6 mice, and found that CBC data were almost the same as those of the mice treated with AraC alone. We next produced humanized chimeric-anti-human VLA4 Ab (chimeric-VLA4Ab), and examined its efficacy in combination with anti-cancer drugs in vitro and in vivo (human leukemia SCID mouse model). Chimeric-VLA4Abs were produced as follows: (i) total RNA of mouse VLA4 Abs were extracted from two hybridomas (SG/17 and SG/73), (ii) cDNA were synthesized by reverse transcriptase, (iii) variable region gene of mouse VLA4 Abs were amplified by 5′RACE method, (iv) TA cloning of amplified gene was performed, (v) sequence of mouse VLA4Abs gene was determined, (v) cloned variable region gene of mouse VLA4 Abs and constant region gene of human IgG1 were inserted into expression vector, and the expression vector was transfected into 293T cells, (vi) supernatant of the 293T cells was collected and purified to obtain chimeric-VLA4 Abs. The effects of chimeric-VLA4 Abs thus obtained in in vitro and in vivo (human leukemia SCID mouse model) were comparable to those of mouse VLA4 Abs. To perform the clinical study, we are presently producing the GMP-graded chimeric-VLA4 Abs.

scholarly journals The Novel Synthetic Peptide AESIS-1 Exerts a Preventive Effect on Collagen-Induced Arthritis Mouse Model via STAT3 Suppression

2020 ◽  
Vol 21 (2) ◽  
pp. 378
Author(s):  
Kyung Eun Kim ◽  
Suwon Jeon ◽  
Jisun Song ◽  
Tae Sung Kim ◽  
Min Kyung Jung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Synthetic Peptide ◽  
Specific Inhibitor ◽  
Cytokine Signaling ◽  
The Novel ◽  
Collagen Induced Arthritis ◽  
Stat3 Phosphorylation ◽  
And Cartilage

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.

scholarly journals An Updated Review of Smac Mimetics, LCL161, Birinapant, and GDC-0152 in Cancer Treatment

2020 ◽  
Vol 11 (1) ◽  
pp. 335
Author(s):  
Yung-Chieh Chang ◽  
Chun Hei Antonio Cheung
Keyword(s):  
Cancer Treatment ◽  
Phase 1 ◽  
The Novel ◽  
Iap Antagonist ◽  
Anti Cancer ◽  
Smac Mimetics ◽  
Molecular Mechanism Of Action ◽  
Apoptosis Proteins

Inhibitor of apoptosis proteins (IAPs) are suggested as therapeutic targets for cancer treatment. Smac/DIABLO is a natural IAP antagonist in cells; therefore, Smac mimetics have been developed for cancer treatment in the past decade. In this article, we review the anti-cancer potency and novel molecular targets of LCL161, birinapant, and GDC-0152. Preclinical studies demonstrated that Smac mimetics not only induce apoptosis but also arrest cell cycle, induce necroptosis, and induce immune storm in vitro and in vivo. The safety and tolerance of Smac mimetics are evaluated in phase 1 and phase 2 clinical trials. In addition, the combination of Smac mimetics and chemotherapeutic compounds was reported to improve anti-cancer effects. Interestingly, the novel anti-cancer molecular mechanism of action of Smac mimetics was reported in recent studies, suggesting that many unknown functions of Smac mimetics still need to be revealed. Exploring these currently unknown signaling pathways is important to provide hints for the modification and combination therapy of further compounds.

LC-MS/MS identification of the principal in vitro and in vivo phase I metabolites of the novel thiosemicarbazone anti-cancer drug, Bp4eT

2012 ◽  
Vol 403 (1) ◽  
pp. 309-321 ◽  
Author(s):  
Ján Stariat ◽  
Vít Šesták ◽  
Kateřina Vávrová ◽  
Milan Nobilis ◽  
Zuzana Kollárová ◽  
...  
Keyword(s):  
Phase I ◽  
Cancer Drug ◽  
The Novel ◽  
Anti Cancer

Can Kampo medicine prolong the life of metastatic colorectal cancer (MCRC) patients with chemotherapy?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15120-e15120
Author(s):  
K. Sasaki ◽  
K. Oono ◽  
K. Harada ◽  
T. Someya ◽  
Y. Takada ◽  
...  
Keyword(s):  
Low Cost ◽  
Survival Rates ◽  
Kampo Medicine ◽  
Tumor Characteristics ◽  
Treatment Groups ◽  
Anti Cancer ◽  
Group A ◽  
Group B

e15120 Background: Many in vivo and in vitro studies have shown that Kampo medicine has various biological and immunological activities, including anti-cancer effect. However, we have little data on efficacy of survival period on MCRC patients (pts) with chemotherapy and Kampo therapy. The aim of this study was to evaluate the survival benefit on MCRC pts treated with Kampo medicine and chemotherapy. Methods: From 2002 to 2007, we treated 66 patients with MCRC. These patients were treated with chemotherapy (CPT-11 + S-1) and/or Kampo medicine (Jyuzen-Taiho-To, TJ-48) on out-patient basis. TJ-48 was given orally at a dose of 7.5g, three times daily. We randomly divided the MCRC pts following two treatment groups; chemotherapy plus Kampo medicine (Group A, n=33) and chemotherapy only (Group B, n=33). Results: Pts and tumor characteristics were much the same between the two groups at baseline. Pts treated with Kampo medicine in combination with chemotherapy (Group A) had a median survival of 20.5 months compared with 15 months for Group B (p=0.12). One and 2 years survival rates were 72% and 13%. No toxic death was reported. The overall 1, 2 and 3 years survival rate were 69, 24 and 12% respectively in Group A, 57, 0 and 0% in Group B. Adverse events did not increase in Group A. TJ-48 is low cost medicine ($1.8 / day). All patients were treated on an out-patient clinic. Conclusions: These results confirmed that the Kampo medicine is helpful and capable of prolonging the survival periods in pts with MCRC. No significant financial relationships to disclose.

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