Monensin-mediated growth inhibition of SNU-C1 colon cancer cells via cell cycle arrest and apoptosis

Park, Woo Hyun; Kim, Eun Shil; Jung, Chul Won; Kim, Byoung Kook; Lee, Young Yiul

doi:10.3892/ijo.22.2.377

Cited by 36 publications

(29 citation statements)

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“…Studies in cultured cells indicate that DSF inhibits myeloma, leukemia, lymphoma, small cell lung cancer, cervical adenocarcinoma, melanoma, neuroblastoma, and colorectal cancer cell survival as well as osteosarcoma invasion (36,37). Monensin in turn has been reported to inhibit myeloma, renal cell carcinoma, colon cancer, lymphoma, and leukemia cell growth in vitro (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

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Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells. Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC 50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro. Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically wellknown molecules can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070-8)

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Section: Discussionmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

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“…Nigericin was also found to have antiproliferative properties in the same screen. Likewise, a half-maximal inhibitory concentration (IC 50 ) of 0.5 μM has been determined for monensin against lymphoma, myeloma, and colon cancer cells (33,34). We hypothesized that the functional similarities of TDA with these polyether drugs might extend to antiproliferative properties.…”

Section: Significancementioning

confidence: 99%

Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink

Wilson

Wang

Gitai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

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While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed.

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“…Female hairless Nu/J mice (Charles River Laboratories) that were 6-to 8-week old were injected subcutaneously with a suspension of SN12C cells (1.0 Â 10 6 ) in a 50% growth factor-reduced Matrigel (BD Biosciences) solution. SN12C tumors were allowed to grow for 1 week before randomization into control (vehicle solution only) and drug (gramicidin A) groups of 5 mice each with an average initial tumor volume of approximately 100 mm 3 , as determined by caliper measurement using the formula [(length Â width 2 )/2] where length was the longest of the two measurements. Gramicidin A (0.11 mg/kg body weight) was diluted in a 1:1 solution of ethanol and saline (0.9% NaCl), and mice were dosed twice weekly with 50 mL of either vehicle or gramicidin A solutions by intratumoral injection.…”

Section: Tumor Growth Assaymentioning

confidence: 99%

“…When the tumors reached an average size of approximately 100 mm 3 , the mice were randomized into two groups (n ¼ 5)…”

Section: Gramicidin a Induces Metabolic Dysfunction In Rcc Cellsmentioning

confidence: 99%

Gramicidin A Induces Metabolic Dysfunction and Energy Depletion Leading to Cell Death in Renal Cell Carcinoma Cells

David

Owens

Barwe

et al. 2013

Molecular Cancer Therapeutics

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Ionophores are lipid-soluble organic molecules that disrupt cellular transmembrane potential by rendering biologic membranes permeable to specific ions. They include mobile-carriers that complex with metal cations and channel-formers that insert into the membrane to form hydrophilic pores. Although mobile-carriers possess anticancer properties, investigations on channel-formers are limited. Here, we used the channelforming ionophore gramicidin A to study its effects on the growth and survival of renal cell carcinoma (RCC) cells. RCC is a histologically heterogeneous malignancy that is highly resistant to conventional treatments. We found that gramicidin A reduced the in vitro viability of several RCC cell lines at submicromolar concentrations (all IC 50 < 1.0 mmol/L). Gramicidin A exhibited similar toxicity in RCC cells regardless of histologic subtype or the expression of either the von Hippel-Lindau tumor suppressor gene or its downstream target, hypoxiainducible factor-1a. Gramicidin A decreased cell viability equal to or greater than the mobile-carrier monensin depending on the cell line. Mechanistic examination revealed that gramicidin A blocks ATP generation by inhibiting oxidative phosphorylation and glycolysis, leading to cellular energy depletion and nonapoptotic cell death. Finally, gramicidin A effectively reduced the growth of RCC tumor xenografts in vivo. These results show a novel application of gramicidin A as a potential therapeutic agent for RCC therapy.

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Monensin-mediated growth inhibition of SNU-C1 colon cancer cells via cell cycle arrest and apoptosis

Cited by 36 publications

References 0 publications

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink

Gramicidin A Induces Metabolic Dysfunction and Energy Depletion Leading to Cell Death in Renal Cell Carcinoma Cells

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