Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

Abstract Background: Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. In this study, we examined Amiodarone's effects on glioblastoma multiforme (GBM), a highly aggressive and hypervascularized cancer. We hypothesized that Amiodarone would show an anti-angiogenic effect on GBM in addition to its previously suggested anti-cancer activity, and that an ultra-low dose would be both effective and possibly avert the drug’s side effects. Methods: The anti-cancer activity of Amiodarone was assessed by several in vitro assays using GBM cells. This included cytotoxicity, proliferation, transwell migration, Anoikis, colony-formation and three-dimensional (3D) spheroid growth assays. The anti-angiogenic effect of Amiodarone was tested on endothelial cells, using toxicity, proliferation, migration and tube formation in vitro assays. The anti-cancer and anti-angiogenic activity of Amiodarone was examined in vivo on three different murine models. C57BL/6J mice were utilized for the corneal neovascularization model and the Matrigel plug assay. Foxn1 nu mice were inoculated with GBM cells and used for the GBM tumor xenograft model.Results: In this study, we showed that Amiodarone has a significant anti-cancer and anti-angiogenic activity in vitro. Moreover, ultra-low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect in vivo. Conclusions: Our results strongly suggest that Amiodarone possess dual cancer fighting properties.

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Low dose amiodarone reduces tumor growth and angiogenesis

Scientific Reports ◽

10.1038/s41598-020-75142-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Eliana Steinberg ◽

Arnon Fluksman ◽

Chalom Zemmour ◽

Katerina Tischenko ◽

Adi Karsch-Bluman ◽

...

Keyword(s):

Side Effects ◽

Cancer Cells ◽

Low Dose ◽

Tumor Model ◽

In Vitro Assays ◽

Potential Candidate ◽

Key Factor ◽

Angiogenic Effect

Abstract Amiodarone is an anti-arrhythmic drug that was approved by the US Food and Drug Administration (FDA) in 1985. Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. However, it is also known to cause a variety of severe side effects. We hypothesized that in addition to the cytotoxic effects observed in cancer cells Amiodarone also has an indirect effect on angiogensis, a key factor in the tumor microenvironment. In this study, we examined Amiodarone's effects on a murine tumor model comprised of U-87 MG glioblastoma multiforme (GBM) cells, known to form highly vascularized tumors. We performed several in vitro assays using tumor and endothelial cells, along with in vivo assays utilizing three murine models. Low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect, suggesting dual cancer fighting properties. Our findings lay the ground for further research of Amiodarone as a possible clinical agent that, used in safe doses, maintains its dual properties while averting the drug’s harmful side effects.

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Anticancer activity of the selective CYP17A1 inhibitor, VT-464, in preclinical models of castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.104 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 104-104 ◽

Cited By ~ 1

Author(s):

Paul Toren ◽

Steven Pham ◽

Soojin Kim ◽

Hans Adomat ◽

Amina Zoubeidi ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Xenograft Model ◽

Resistant Cell ◽

Anti Cancer ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Cancer Activity

104 Background: Castrate resistant prostate cancer (CRPC) continues to be sensitive to anti-androgen therapy as evidenced by the recent successes of abiraterone acetate (AA) and enzalutamide (ENZ). VT-464 is a novel, non-steroidal, small molecule CYP17A1 inhibitor with selectivity for the lyase activity of this dual enzyme. The objective of this study was to evaluate the anti-cancer activity of VT-464 compared to AA in CRPC in vitro models that are ENZ-responsive and ENZ-resistant and in an ENZ-resistant xenograft model. Methods: In vitro studies used the human CRPC, C4-2, and ENZ-resistant cell lines, MR49C and MR49F cells, in androgen-free media. AR transcriptional activity was assessed by probasin luciferase. AR-related and steroidogenesis pathways were assessed by western blot and/or qRT-PCR. A MR49F xenograft model in castrate mice compared oral VT-464 treatment to vehicle and AA. Steroid concentrations were measured using LC-MS chromatography. Results: VT-464 demonstrated a greater decrease in AR transactivation compared to AA in C4-2 and both ENZ-resistant cell lines. A greater decrease in AR-dependent gene transcription occurred with VT-464 treatment compared to AA in all cell lines. Prostate-specific antigen (PSA) protein levels in vitro were also lower with VT-464. Gene transcripts StAR, CYP17A1, HSD17B3 and SRD5A1 increased following treatment with VT-464 both in vitro and in vivo. A greater increase was seen with VT-464 treatment compared to AA. In vivo results demonstrated greater tumor growth inhibition and decreased serum PSA levels in mice treated with oral VT-464 compared to AA. Steroid analysis revealed lower testosterone (T) and dihydrotestosterone (DHT) concentrations in C4-2 cells with VT-464 treatment compared to AA. In vivo, the intra-tumoral DHT and T levels were significantly lower in response to VT-464 or AA compared to vehicle, with the greatest decrease seen with VT-464. Conclusions: The selective CYP17 inhibitor VT-464 demonstrated anti-cancer activity in pre-clinical models of CRPC, lowering intratumoral T and DHT concentrations significantly in castrate mice. These results suggest greater androgen suppression and inhibition of AR axis signaling by VT-464 than by AA.

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Evaluation of the anti-cancer activity of the triterpenoidal saponin fraction isolated from the traditional Chinese medicine Conyza blinii H. Lév.

RSC Advances ◽

10.1039/c6ra26361e ◽

2017 ◽

Vol 7 (6) ◽

pp. 3408-3412 ◽

Cited By ~ 11

Author(s):

Long Ma ◽

Haiyan Liu ◽

Lingpei Meng ◽

Ping Qin ◽

Botao Zhang ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Anti Cancer ◽

Saponin Fraction ◽

Cancer Activity

Triterpenoidal saponins fraction isolated from a traditional Chinese medicine Conyza blinii H. Lév. demonstrates anti-cancer activity both in vitro and in vivo.

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Novel eIF4E/eIF4G protein-protein interaction inhibitors DDH-1 exhibits anti-cancer activity in vivo and in vitro

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2020.05.233 ◽

2020 ◽

Vol 160 ◽

pp. 496-505 ◽

Cited By ~ 1

Author(s):

Jun Wang ◽

Lijun Wang ◽

Shuhong Zhang ◽

Junting Fan ◽

Hui Yang ◽

...

Keyword(s):

Protein Interaction ◽

Protein Protein Interaction ◽

Anti Cancer ◽

Cancer Activity

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Mechanism of action of the third generation benzopyrans and evaluation of their broad anti-cancer activity in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-018-22882-w ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 5

Author(s):

Alexander J. Stevenson ◽

Eleanor I. Ager ◽

Martina A. Proctor ◽

Dubravka Škalamera ◽

Andrew Heaton ◽

...

Keyword(s):

Mechanism Of Action ◽

Third Generation ◽

The Third ◽

Anti Cancer ◽

Cancer Activity

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Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

International Journal of Molecular Sciences ◽

10.3390/ijms21186672 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6672

Author(s):

Zora Novakova ◽

Nikola Belousova ◽

Catherine A. Foss ◽

Barbora Havlinova ◽

Marketa Gresova ◽

...

Keyword(s):

Functional Characterization ◽

Xenograft Model ◽

In Vitro Assays ◽

Experimental Therapy ◽

Single Chain ◽

Single Chain Fv ◽

Murine Xenograft Model ◽

Single Target

Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use.

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Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Cancers ◽

10.3390/cancers11101550 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1550 ◽

Cited By ~ 2

Author(s):

Tomomi Sanomachi ◽

Shuhei Suzuki ◽

Keita Togashi ◽

Asuka Sugai ◽

Shizuka Seino ◽

...

Keyword(s):

Cancer Cells ◽

Kinase Inhibitors ◽

Xenograft Model ◽

Growth Factor Receptor ◽

Survivin Expression ◽

Mouse Xenograft Model ◽

Anti Cancer ◽

Underlying Mechanisms

Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

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

TECHNOLOGY ◽

10.1142/s2339547816500011 ◽

2016 ◽

Vol 04 (01) ◽

pp. 60-69 ◽

Cited By ~ 7

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.

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Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma

Cell Death and Disease ◽

10.1038/s41419-020-03126-0 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Qinchao Hu ◽

Jianmin Peng ◽

Laibo Jiang ◽

Wuguo Li ◽

Qiao Su ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Xenograft Model ◽

Neck Squamous Cell Carcinoma ◽

In Vitro Assays ◽

Anticancer Efficacy

Abstract CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated β-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and stat3 pathways. The LY2835219-induced SASP resulted in upregulation of cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.

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