scholarly journals Cytotoxic effect of Montivipera bornmuelleri’s venom on cancer cell lines: in vitro and in vivo studies

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9909
Author(s):  
Carol Haddoub ◽  
Mohamad Rima ◽  
Sandrine Heurtebise ◽  
Myriam Lawand ◽  
Dania Jundi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
In Vivo Testing ◽  
Murine Fibrosarcoma ◽  
Dose Dependent

Background Montivipera bornmuelleri’s venom has shown immunomodulation of cytokines release in mice and selective cytotoxicity on cancer cells in a dose-dependent manner, highlighting an anticancer potential. Here, we extend these findings by elucidating the sensitivity of murine B16 skin melanoma and 3-MCA-induced murine fibrosarcoma cell lines to M. bornmuelleri’s venom and its effect on tumor growth in vivo. Methods The toxicity of the venom on B16 and MCA cells was assessed using flow cytometry and xCELLigence assays. For in vivo testing, tumor growth was followed in mice after intratumoral venom injection. Results The venom toxicity showed a dose-dependent cell death on both B16 and MCA cells. Interestingly, overexpression of ovalbumin increased the sensitivity of the cells to the venom. However, the venom was not able to eradicate induced-tumor growth when injected at 100 µg/kg. Our study demonstrates a cytotoxic effect of M. bornmuelleri’s venom in vitro which, however, does not translate to an anticancer action in vivo.

Studies of pemetrexed and gemcitabine, alone and in combinations, in human lung cancer models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17114-17114 ◽  
Author(s):  
D. C. Chan ◽  
V. J. Chen ◽  
Z. Zhang ◽  
B. Helfrich ◽  
F. R. Hirsch ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
In Vivo Studies ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Nude Rats ◽  
Combination Regimens

17114 Background: Gemcitabine (GEM) is a deoxycytidine analog that inhibits DNA synthesis. Pemetrexed (ALIMTA, PEM) is a novel antifolate inhibiting multiple enzymes targets, including thymidylate synthase (TS). This study aimed at evaluating the antitumor effects of these antimetabolites against NSCLC and SCLC tumor models. Methods: In vitro growth inhibition (IC50) studies were done by 6-days MTT assays against a panel of 20 NSCLC and 17 SCLC cell lines. In vivo studies used only NSCLC H2122 tumor line, implanted either subcutaneously in athymic nude mice or orthotopically in athymic nude rats. Drugs were given via the ip route at the designated schedules. Results: Against NSCLC and SCLC cell lines, the averaged IC50s of GEM were 0.015 ± 0.008 μM and 0.055 ± 0.04 μM respectively. The corresponding averaged IC50s for PEM were 0.65 ± 0.2 μM and 0.091±0.018 μM respectively. When H2122 tumors reached 50–100mg, mice were treated with 10 daily doses of PEM at 100, 200 and 300 mg/kg, or three doses of GEM every 4 days at 30, 60 and 120 mg/kg. PEM delayed tumor growth by 12 to 18 days, and GEM delayed by 10 to 14 days, relative to vehicle control. Results of three combination regimens with GEM (30 mg/kg) and PEM (100 mg/kg) were: (1) GEM → PEM gave intermediate activities between the two single agents, but was toxic to animals; (2) PEM and GEM given concurrently were more active than single agents alone and delayed tumor growth by 12 days with some toxic side effects; (3) PEM → GEM was better than the single agents alone, and delayed tumor growth by ∼14 days without toxicity. Athymic nude rats bearing orthotopic H2122 tumors given PEM daily at 50, 100 and 200 mg/kg for 21 days had significantly prolonged survival, but not in a dose-dependent manner. PEM at 50 mg/kg was more effective than doses at 100 or 200 mg/kg. GEM was toxic to nude rats due to poor plasma deamination of GEM. Conclusions: In vitro, PEM was more potent against SCLC than NSCLC cell lines, but GEM had similar activities against all lung lines tested. Studies of H2122 xenografts in rodent supported PEM → GEM as the preferred sequence for the combined administration of these two drugs. [Table: see text]

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 205-205
Author(s):  
Thomas Nelius ◽  
Courtney Jarvis ◽  
Dalia Martinez-Marin ◽  
Stephanie Filleur
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Raw264.7 Macrophages

205 Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.

Small Molecule Inhibitor of ITK Disrupts TCR Signaling and Demonstrates Anti-Tumor Efficacy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3932-3932
Author(s):  
Mary Faris ◽  
Uriel M Malyankar ◽  
Qingping Zeng ◽  
Gary A Flynn ◽  
Gerold Feuer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
T Cell Malignancies ◽  
Dose Dependent ◽  
Leukemias And Lymphomas

Abstract Abstract 3932 ITK (Interluekin-2 Inducible Tyrosine Kinase) is a member of the TEC family of intracellular protein tyrosine kinases. ITK is highly expressed in T cells and NK cells, with expression detected in mast cells. ITK plays a key role in several aspects of T cell biology, including T cell development, differentiation, migration, proliferation and activation. The function of ITK in immunity and allergy is well documented. T cells from ITK knock out mice show several developmental and functional defects, including defective signal transduction, altered CD4+ to CD8+ T cells ratios, reduced Th2 lineage differentiation, diminished IL4 and IL2 production and reduced T cell proliferation. Importantly ITK deficient mice fail to mount an immune response to infection and show reduced allergic asthma reactions. In contrast to its well described role in immune function, ITK's function in cancer biology is still emerging. Recent studies had reported enhanced ITK expression and activation of the ITK pathway in several types of leukemias and lymphomas. In addition, the dependence of T cell malignancies on an ITK-regulated pathway, namely the IL2/IL2R (CD25) pathway, has also been observed. Taken together, this information indicates that ITK is a therapeutic target, with applicability in leukemias and lymphomas. MannKind scientists have developed a series of selective small molecule ITK inhibitors, including the orally available tool compound described within, and evaluated their activity in enzyme, cell-based and in vivo studies. In cellular assays, the compounds showed significant inhibition of the T cell-receptor mediated activation of the ITK pathways and related downstream cytokine production. In addition to inhibiting the phosphorylation of ITK and its downstream mediator, PLCg, our tool compounds inhibited the production of IL2 and expression of CD25 in a dose dependent manner. Importantly, our compound regulated the in vitro growth of tumor T cells but not that of unrelated control cells. In vivo studies revealed that the tool compounds inhibited the growth and progression of patient derived ATL tumors in a xenograft pre-clinical model, and prolonged the survival of treated mice in a dose dependent manner, in addition to regulating cytokine production in vivo. In summary, our team has identified ITK selective compounds with demonstrated on-target and anti-tumor activity in vitro and preclinical T cell tumor models, and validated this pathway relative to T cell malignancies. This effort provides a platform for further compound optimization and evaluation for hematologic malignancies. Disclosures: Faris: MannKind Corp: Employment. Malyankar:MannKind Corp: Employment. Zeng:MannKind Corp: Employment. Kertesz:Mannkind Corporation: Employment, Equity Ownership. Vuga:MannKind Corp.: Employment. Rosario:MannKind Corp: Employment. Bot:MannKind Corp: Employment.

Use of verapamil to enhance the antiproliferative activity of BCNU in human glioma cells: an in vitro and in vivo study

1990 ◽  
Vol 73 (2) ◽  
pp. 248-253 ◽  
Author(s):  
Alfred P. Bowles ◽  
Cooley G. Pantazis ◽  
William Wansley
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Human Glioma ◽  
Content Type ◽  
Brain Tumor Cells ◽  
Inhibition Of Tumor Growth ◽  
Dose Dependent

✓ The authors have evaluated the antiproliferative activity of verapamil, alone or in combination with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in brain-tumor cells. These effects were studied in vitro using four human glioma cell lines and in vivo using glioblastoma multiforme cells transplanted to athymic nude mice. The results showed that verapamil when used alone produced inhibition of tumor growth; however, when verapamil was used in combination with BCNU (in vitro), significant dose-dependent suppression of proliferation occurred in all four cell lines. The in vivo results were far more dramatic. Mice treated with BCNU (25 mg/kg) plus verapamil (50 mg/kg) achieved a 200-fold decrease in tumor growth with a greater than 80% regression in tumor size. Complete cures were achieved in 80% of the mice observed for at least 50 days following the completion of therapy. These findings support the use of verapamil in overcoming drug resistance in malignant brain tumors.

scholarly journals Strong Antifungal Activity of SS750, a New Triazole Derivative, Is Based on Its Selective Binding Affinity to Cytochrome P450 of Fungi

2002 ◽  
Vol 46 (2) ◽  
pp. 308-314 ◽  
Author(s):  
Masaru Matsumoto ◽  
Kazuya Ishida ◽  
Akihiro Konagai ◽  
Kazunori Maebashi ◽  
Takemitsu Asaoka
Keyword(s):  
Cytochrome P450 ◽  
Antifungal Activity ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Strong Affinity ◽  
Dose Dependent ◽  
Potent Inhibitory Activity ◽  
In Vitro Antifungal Activity

ABSTRACT SS750 [(R)-(−)-2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol] is a new triazole, and its potential as an antifungal agent was evaluated by in vitro and in vivo studies. In a comparison of the MICs at which 50% of isolates are inhibited (MIC50s) for all strains of Candida species and Cryptococcus neoformans tested, SS750 was four times or more active than fluconazole and had activity comparable to that of itraconazole. The most important advantage of SS750 was that, when the MIC90s were compared, SS750 had 64 and 32 times greater antifungal activities than fluconazole against Candida krusei and Candida glabrata, respectively, which are intrinsically less susceptible to fluconazole. In cyclophosphamide-immunosuppressed mouse models of systemic and pulmonary candidiasis caused by C. albicans, oral SS750 prolonged the number of days of survival of infected animals in a dose-dependent manner and was 4 and ≥64 times more potent than fluconazole and itraconazole, respectively. In a safety profile, SS750, like fluconazole, had less of an affinity for binding to mammalian cytochrome P450 compared with that of ketoconazole, despite its strong affinity for binding to fungal cytochrome P450. The mechanism for the increased in vitro antifungal activity of SS750 against C. krusei is partially due to the potent inhibitory activity (3.7 times versus that of fluconazole) of C. krusei cytochrome P450 sterol 14α-demethylase; SS750 showed a strong affinity for binding to cytochrome P450 of C. krusei, indicating that SS750 acts by inhibiting the cytochrome P450 sterol 14α-demethylase of fungal cells.

scholarly journals PEG10 is associated with treatment-induced neuroendocrine prostate cancer

2019 ◽  
Vol 63 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Soojin Kim ◽  
Daksh Thaper ◽  
Samir Bidnur ◽  
Paul Toren ◽  
Shusuke Akamatsu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Resistant Cell ◽  
Dependent Manner ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Marker Status ◽  
Dose Dependent

Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.

Antagonist Anti-CD40 Antibody CHIR-12.12 Causes Tumor Regression and Prolongs Survival in Multiple Myeloma Xenograft Models.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4888-4888
Author(s):  
Li Long ◽  
Xia Tong ◽  
Montesa Patawaran ◽  
Lea Aukerman ◽  
Bahija Jallal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Volume ◽  
Dependent Manner ◽  
Human Multiple Myeloma ◽  
Xenograft Models ◽  
Dose Dependent

Abstract CD40 is expressed on most B cell malignancies including multiple myeloma and represents an attractive target for antibody therapy. We have generated a novel, highly potent, fully human antagonistic anti-CD40 monoclonal antibody, CHIR-12.12, using XenoMouse® mice (Abgenix, Inc). The antibody can mediate anti-tumor activity potentially by at least two mechanisms: CHIR-12.12 can block CD40-ligand mediated survival signals and it can lyse tumor cells by antibody-dependent cellular cytotoxicity (ADCC). We have previously reported that CHIR-12.12 mediates stronger killing of CD40- and CD20-expressing lymphoma cells than rituximab by ADCC in vitro and significantly inhibits the growth of both rituximab-responsive and rituximab-resistant human lymphoma xenografts in vivo. In this study, we examined in vitro and in vivo efficacy of CHIR-12.12 against human multiple myeloma. The human MM cell line IM-9, which expresses both CD40 and CD20, the target antigen for CHIR-12.12 and rituximab respectively was used for the study. CHIR-12.12 induced lysis of target tumor cells by ADCC in a dose dependent manner reaching maximum cell lysis at 0.1ug/ml concentration. The maximum specific lysis of IM-9 cells by CHIR-12.12 was greater than the lysis induced by rituximab (64% vs 45 %, n=3, p<0.01). In addition, the EC50 of CHIR-12.12 was on average 5.9 picomolar, which was 10-fold lower than the EC50 of rituximab. Greater ADCC by CHIR-12.12 was not due to higher density of CD40 molecules on the target tumor cells compared to CD20 molecules. IM-9 cells expressed 35590 ±8858 CD40 molecules compared to 93783 ± 2247 CD20 molecules. The in vivo CHIR-12.12 efficacy was then evaluated in IM-9 xenograft model. In an un-staged conditional survival model, where treatment began one day after intravenous inoculation of IM-9 tumor cells, CHIR-12.12 significantly prolonged the survival of tumor-bearing mice in a dose-dependent manner with 60% survival in the 0.1 mg/kg CHIR-12.12 treated group and 80% survival in the 1 and 10 mg/kg groups respectively on day 56 (Log Rank Test: P<0.01 and P<0.001, respectively). All animals in the control IgG1 and bortezomib treated groups were terminated between day 18 and day 26 due to severe disease related to tumor development (i.e., hind limb paralysis and significant body weight loss). In a staged subcutaneous model, where treatment began once the tumor volume was 150–200mm3, CHIR-12.12 administered weekly at 0.1, 1 and 10 mg/kg significantly inhibited tumor growth with a tumor volume reduction of 17% (P>0.05), 34% (P<0.01) and 44% (P<0.001) respectively. Bortezomib, when tested at 0.5 mg/kg twice a week did not inhibit tumor growth. At the maximally tolerated dose (MTD) of 1 mg/kg twice a week, bortezomib inhibited tumor growth by 30% (P<0.01). Taken together, these data demonstrate that the anti-CD40 mAb CHIR-12.12 has potent activity against human multiple myeloma in vitro and xenograft models in vivo.

Antagonist Anti-CD40 Antibody, CHIR-12.12, Induces ADCC, Inhibits Tumor Growth, and Prolongs Survival in a Human Multiple Myeloma Xenograft Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3470-3470 ◽  
Author(s):  
Li Long ◽  
Xia Tong ◽  
Montesa Patawaran ◽  
Sharon L. Aukerman ◽  
Bahija Jallal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Growth ◽  
B Cell ◽  
Median Survival ◽  
Dependent Manner ◽  
Human Multiple Myeloma ◽  
Xenograft Models ◽  
Dose Dependent

Abstract CD40 is expressed on all B-cell malignancies, including multiple myeloma, and represents an attractive target for antibody therapy. CHIR-12.12 is a fully human, highly potent, IgG1 antagonistic anti-CD40 monoclonal antibody generated using XenoMouse® mice (Abgenix, Inc). CHIR-12.12 can mediate antitumor activity by at least two mechanisms: blocking CD40-ligand-mediated survival signals and killing tumor cells by antibody-dependent cellular cytotoxicity (ADCC). We have previously reported that CHIR-12.12 mediates stronger in vitro killing of CD40+- and CD20+-expressing human non-Hodgkin’s lymphoma and lymphoblastoid B cells by ADCC than rituximab and significantly inhibits the growth of rituximab-responsive (Daudi) and rituximab-resistant (Namalwa) human lymphoma and lymphoblastoid B-cell (IM-9) xenografts in vivo. In this study, we examined the in vitro and in vivo efficacy of CHIR-12.12 against the human multiple myeloma cell line KMS-12-BM. CHIR-12.12 induced lysis of KMS-12-BM cells by ADCC in a dose-dependent manner, reaching maximum cell lysis at 0.1μg/ml with an EC50 of 17.5 pM. CHIR-12.12 efficacy in vivo was evaluated in orthotopic and subcutaneous KMS-12-BM xenograft models. In the staged orthotopic model, tumor cells were delivered intravenously and treatment was initiated 7 days post cell implantation. CHIR-12.12 significantly prolonged the median survival of tumor-bearing mice in a dose-dependent manner, with a median survival of 78 and 98 days in the groups treated with 1 mg/kg and 10 mg/kg CHIR-12.12 weekly, respectively, compared to a median survival time of 68 days in the control IgG1 group (P<0.0001). Bortezomib administered i.v. twice weekly at 0.5 or 1 mg/kg showed no survival benefit. In the staged subcutaneous model, CHIR-12.12 was administered weekly at 1 and 10 mg/kg after the mean tumor volume reached 100mm3. CHIR-12.12 significantly inhibited tumor growth, with a tumor volume reduction of 42% (P<0.05) and 63% (P<0.01), respectively. Bortezomib and melphalan/prednisone did not inhibit KMS-12-BM tumor growth at the doses and schedules reported for other human multiple myeloma xenograft models. Western blot analysis and immunohistochemical staining showed significantly increased levels of cleaved PARP in KMS-12-BM s.c. tumors 7 days after the initiation of CHIR-12.12 treatment, suggesting the induction of cell death by CHIR-12.12. Taken together, these data demonstrate that the anti-CD40 mAb CHIR-12.12 has potent activity against human multiple myeloma cells in vitro and in xenograft models in vivo. Currently CHIR-12.12 is in Phase I clinical trials for the treatment of B-cell malignancies.

scholarly journals Blockage of Cholinergic Signaling via Muscarinic Acetylcholine Receptor 3 Inhibits Tumor Growth in Human Colorectal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3220
Author(s):  
Nina A. Hering ◽  
Verena Liu ◽  
Rayoung Kim ◽  
Benjamin Weixler ◽  
Raoul A. Droeser ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Acetylcholine Receptor ◽  
Tumor Therapy ◽  
Muscarinic Acetylcholine Receptor ◽  
Dependent Manner ◽  
Matrigel Invasion ◽  
Cholinergic Signaling ◽  
Dose Dependent

Cholinergic signaling via the muscarinic M3 acetylcholine receptor (M3R) is involved in the development and progression of colorectal cancer (CRC). The present study aimed to analyze the blocking of M3R signaling in CRC using darifenacin, a selective M3R antagonist. Darifenacin effects were studied on HT-29 and SW480 CRC cells using MTT and BrdU assays, Western blotting and real time RT-PCR. In vivo, blocking of M3R was assessed in an orthotopic CRC xenograft BALB/cnu/nu mouse model. M3R expression in clinical tumor specimens was studied by immunohistochemistry on a tissue microarray of 585 CRC patients. In vitro, darifenacin decreased tumor cell survival and proliferation in a dose-dependent manner. Acetylcholine-induced p38, ERK1/2 and Akt signaling, and MMP-1 mRNA expression were decreased by darifenacin, as well as matrigel invasion of tumor cells. In mice, darifenacin reduced primary tumor volume and weight (p < 0.05), as well as liver metastases, compared to controls. High expression scores of M3R were found on 89.2% of clinical CRC samples and correlated with infiltrative tumor border and non-mucinous histology (p < 0.05). In conclusion, darifenacin inhibited components of tumor growth and progression in vitro and reduced tumor growth in vivo. Its target, M3R, was expressed on the majority of CRC. Thus, repurposing darifenacin may be an attractive addition to systemic tumor therapy in CRC patients expressing M3R.

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