Low-dose curcumin leads to the inhibition of tumor growth via enhancing CTL-mediated antitumor immunity

e15515 Background: Paclitaxel (PXL) was converted to paclitaxel orotate (PXLO). Different combinations of Carboxyamidotriazole orotate (CTO) and PXL or PXLO were first evaluated in female non-tumored athymic NCr-nu/nu mice to determine the tolerance of the combinations. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated calcium channel-mediated calcium influx. CTO can inhibit calcium sensitive signal transduction in the VEGF and the PI3K pathways, and inhibit FGF-2-induced tyrosine kinase. Methods: The antitumor effect of combinations was tested for: i) PXLO compared to PXL, ii) combinatorial effect of low (342mg/kg/dose) and high (513mg/kg/dose) doses of CTO (Q1Dx14, PO) with low (11.6 and 10mg/kg/inj, Q2Dx3/2 weeks, IV) and high (23.2 and 20mg/kg/inj, Q2Dx3/2 weeks, IV) respectively, doses of PXLO or PXL, against sc-implanted human OVCAR-5 ovarian tumor xenografts. Results: Results obtained in non-tumored mice show high PXLO plus CTO was better tolerated than high PXL plus CTO. In tumor bearing mice, oral CTO at doses of 513 or 342mg/kg/dose Q1Dx14 given alone resulted in slight inhibition of tumor growth, reaching statistical significance only when administered at a low dose (two tumor mass doubling: p=0.036 for 342mg/kg/dose). PXLO at 23.2 and 11.6mg/kg/inj. given alone inhibited tumor growth (p<0.001, 0.029, respectively). PXL at 20 and 10mg/kg/inj inhibited tumor growth (p<0.001 and 0.011, respectively). Since body weight loss was less with the orotate form of PXL, PXLO should be the preferred drug over PXL. Addition of oral CTO 513 or 342mg/kg/dose to PXLO 23.2 or PXL 20mg/kg/inj resulted in comparable tumor inhibition to PXLO or PXL alone. However, combination of PXLO 11.6 and PXL 10mg/kg/inj with CTO 513 or 342mg/kg/dose resulted in tumor inhibition suggesting that a low dose of PXL or PXLO may be combined with CTO to achieve tumor inhibition and to allow the use of the lower doses of PXL to reduce toxicity. Conclusions: Results suggest that PXLO is less toxic than PXL and CTO influences the sensitivity of PXL suggesting a role for combinatorial therapy with low doses of PXL and CTO in this ovarian tumor model.

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In vitro inhibition of tumor growth by low-dose iron oxide nanoparticles activating macrophages

Journal of Biomaterials Applications ◽

10.1177/0885328218817939 ◽

2019 ◽

Vol 33 (7) ◽

pp. 935-945 ◽

Cited By ~ 5

Author(s):

Ling Zhang ◽

Shengwei Tan ◽

Yingxun Liu ◽

Hongmei Xie ◽

Binhua Luo ◽

...

Keyword(s):

Iron Oxide ◽

Magnetic Nanoparticles ◽

Cancer Therapy ◽

Tumor Growth ◽

Low Dose ◽

Cell Counting ◽

Raw264.7 Cells ◽

Control Group ◽

Inhibition Of Tumor Growth

Macrophages as immunocyte are attracting more and more attention in cancer therapy. Our previous study observed that dimercaptosuccinic acid (DMSA)-coated Fe3O4 magnetic nanoparticles triggered comprehensive immune responses of mouse macrophages (RAW264.7 cells) and induced production of many kinds of cytokines. This study investigated the effects of Fe3O4 magnetic nanoparticles on RAW264.7 cells proliferation, migration, and inhibition of tumor growth in vitro. Fe3O4 magnetic nanoparticles had an average size of about 11 nm with good dispersibility and uniformity. Fe3O4 magnetic nanoparticles internalized efficiently into RAW264.7 cells. Through Cell Counting Kit-8 (CCK-8) detection, the proliferation of RAW264.7 cells significantly increased by the low-dose Fe3O4 magnetic nanoparticles (50 µg/mL) treatment. The results of wound-healing and Transwell assays both displayed a significant promotion of the RAW264.7 cells migratory capability compared with control group ( P<0.01). It is interesting to find that a large number of proliferated RAW264.7 cells were activated to surround quickly and attack mouse liver cancer cell (Hepa1-6) cells by Fe3O4 magnetic nanoparticles. The growth of Hepa1-6 cells was effectively inhibited according to microscope imaging and flow cytometry analysis. The inhibition may be cooperative effects of RAW264.7 cells proliferation, migration, and immune activation. The results suggest potential clinical value of low-dose iron oxide nanomaterials in cancer therapy.

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Inhibition of tumor growth of cervical cancer cell line in a murine xenograft model by thalidomide

Geburtshilfe und Frauenheilkunde ◽

10.1055/s-2006-952205 ◽

2006 ◽

Vol 66 (S 01) ◽

Author(s):

LC Horn ◽

M Hermes ◽

M Wobus ◽

J Schwock ◽

M Brulport ◽

...

Keyword(s):

Cervical Cancer ◽

Tumor Growth ◽

Cell Line ◽

Cancer Cell ◽

Xenograft Model ◽

Cancer Cell Line ◽

Cervical Cancer Cell ◽

Cervical Cancer Cell Line ◽

Murine Xenograft Model ◽

Inhibition Of Tumor Growth

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Faculty Opinions recommendation of Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033297.375237 ◽

2006 ◽

Author(s):

Alvin M Matsumoto

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Receptor Agonist ◽

Liver X Receptor ◽

Athymic Mice ◽

Prostate Cancer Cells ◽

Inhibition Of Tumor Growth ◽

Liver X Receptor Agonist

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DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002054 ◽

2021 ◽

Vol 9 (5) ◽

pp. e002054

Author(s):

Francisco J Cueto ◽

Carlos del Fresno ◽

Paola Brandi ◽

Alexis J. Combes ◽

Elena Hernández-García ◽

...

Keyword(s):

Gene Therapy ◽

Dendritic Cells ◽

Tumor Growth ◽

Antitumor Immunity ◽

Elevated Serum ◽

Dead Cell ◽

Type I ◽

Cross Presentation ◽

Patients With Cancer ◽

Deficient Mice

BackgroundConventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.MethodsB16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.ResultsHere, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.ConclusionDNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

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