A Novel β-Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage

Smith, David M.; Kazi, Aslamuzzaman; Smith, Lisa M.; Long, Timothy E.; Heldreth, Bart; Turos, Edward; Dou, Q. Ping

doi:10.1124/mol.61.6.1348

Cited by 71 publications

(45 citation statements)

References 28 publications

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“…Before infection, HeLa cells were washed with phosphate-buffered saline (PBS), and then co-incubated with PBS-washed bacteria at a multiplicity of infection of 1. Four hours after infection, cytotoxicity was measured by the trypan blue exclusion assay (28). In brief, after gently removing bacteria by aspiration, cells were collected with a cell scraper and stained with 0.4% trypan blue (Wako Pure Chemical Industries, Ltd., Osaka, Japan) for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Cytotoxicity and Enterotoxicity of the Thermostable Direct Hemolysin‐Deletion Mutants of Vibrio parahaemolyticus

Park

Ono

Rokuda

et al. 2004

Microbiology and Immunology

117

101

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Vibrio parahaemolyticus, one of the human-pathogenic vibrios, is a Gram-negative halophilic bacterium that naturally inhabits marine and estuarine environments. The bacterium causes food-borne gastroenteritis, most frequently associated with the consumption of raw or undercooked seafood (1). Consumption of sufficiently high numbers of the organism can cause watery diarrhea, septicemia and even death (7,10). Almost all the clinical isolates of V. parahaemolyticus show β-hemolysis on Wagatsuma agar, a special blood agar medium (24). The hemolysis has been called the Kanagawa-phenomenon (KP), and is considered a good marker to differentiate human pathogenic V. parahaemolyticus from the non-pathogenic strains. To date, the thermostable direct hemolysin (TDH), has been shown to have a role in KP (6,27). In 1988, Honda et al. (9) discovered a new hemolysin in KP-negative clinical V. parahaemolyticus isolates. This hemolysin was referred to as TDH-related hemolysin (TRH). It is immunologically similar to TDH, and shares approximately 67% identity with TDH at the amino acid level (9). TDH and TRH show several common biological properties, such as hemolytic activity, enterotoxicity and cytotoxicity (5,6,8,10,16,17,23,25,29,31). V. parahaemolyticus strains isolated from patients with diarrhea produce TDH or TRH or both, whereas environmental isolates rarely produce these proteins (6, 27). Thus, TDH and TRH have been considered to be involved in the gastrointestinal disorders caused by V. parahaemolyticus (6).Although live V. parahaemolyticus shows cytotoxicity and enterotoxicity (2, 15, 25), the virulence factors responsible for these activities have not been fully elucidated. Recently, we completed the genome sequencing of a KP-positive (TDH-producing) V. parahaemolyticus RIMD2210633 strain (13). In this study, we constructed tdh-deletion mutants from the sequenced RIMD2210633 strain, and examined the hemolytic activity, cytotoxicity and enterotoxicity of the mutant strains Abstract: The thermostable direct hemolysin (TDH) has been proposed to be a major virulence factor of Vibrio parahaemolyticus. We have recently completed the genome sequence of a TDH-producing V. parahaemolyticus strain, RIMD2210633. In this study, we constructed tdh-deletion mutants from the sequenced strain by homologous recombination and analyzed their phenotypes. Although the deletion of both copies of tdh completely abolished the hemolytic activity of the wild-type strain, the deletion did not affect the cytotoxicity to HeLa cells. Enterotoxicity, assayed by the rabbit ileal loop test, was lowered by tdh deletion, but the mutant still showed partial fluid accumulation in rabbit intestine. These results indicate that the cytotoxicity and enterotoxicity of TDH-producing V. parahaemolyticus are not explained by TDH alone, and suggest that an unknown virulence factor(s) could be involved in these pathogenic activities.

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Section: Methodsmentioning

confidence: 99%

Cytotoxicity and Enterotoxicity of the Thermostable Direct Hemolysin‐Deletion Mutants of Vibrio parahaemolyticus

Park

Ono

Rokuda

et al. 2004

Microbiology and Immunology

117

101

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“…al had demonstrated discovered and characterized the apoptosis-inducing properties of a family of novel b-lactam antibiotics against human leukemia, breast, prostate, and headand-neck cancer cells. They found that one particular lead compound (lactam 1) with an N-methylthio group was able toinduce DNA damage and inhibit DNA replication in Jurkat T cells within a 2-h treatment [25].…”

Section: Resultsmentioning

confidence: 99%

Differentialin vitroinhibition effects of some antibiotics on tumor associated carbonic anhydrase isozymes of hCA-IX and hCA-XII

Ozensoy

Arslan

Köçkar

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Recientes estudios indican que una familia de antibióticos lactámicos presenta propiedades que inducen apoptosis contra algunos tipos de cáncer; un ejemplo es el compuesto denominado b-lactama 1 (figura 3), capaz de inducir activación de la caspasa 3 y, por lo tanto, apoptosis; inhibe la replicación de ADN asociado con la inducción de daño del ADN. Los mecanismos de acción aún no están completamente entendidos, pero se sabe que tienen relación con el grupo N-metiltiol y el número de átomos de carbono, el número de áto-mos de carbono en el grupo N-metiltiol es inversamente proporcional a la capacidad inductora de apoptosis, y la sustitución de N-metiltiol por N-benciltiol mostró que disminuye la actividad de inducción de apoptosis (Smith et al, 2002).…”

Section: B-lactamasunclassified

Cellular and molecular effect of antitumor agents

Ramírez-Sánchez¹,

Rivera²

2014

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RESUMENLa biología celular y molecular es un área de investigación de gran impacto y rápido crecimiento, la cual se ha convertido en un punto esencial para el desarrollo de nuevos agentes quimioterapéuticos con niveles bajos de toxicidad, particularmente para el cáncer. Aunque la era de la quimioterapia comenzó en los años 40, actualmente es necesario desarrollar nuevas terapias antitumorales que permitan tener un tratamiento apropiado para cada paciente y tipo de tumor, siendo necesaria la identificación de componentes celulares y moleculares involucrados en los procesos de carcinogénesis, para el desarrollo de agentes quimioterapéu-ticos que intervengan en la restauración o destrucción selectiva de las células cancerígenas. Actualmente, se ha demostrado que ciertos medicamentos, como los antibióticos (tetraciclinas, sulfonamidas y b-lactamas) y otros compuestos químicos (quinoxalinas) que son utilizados con otro fin terapéutico, han presentado efectos anticancerígenos, con una actividad antiproliferativa e inhibitoria, por lo cual pueden ser una nueva opción para el tratamiento farmacológico del cáncer. ABSTRACTCellular and molecular biology is a research field with high impact and fast growth; it becomes essential for the development of new chemotherapeutic agents with low toxicity, particularly against cancer. Although chemotherapy era began in the 40's, it has been necessary to development new antitumoral therapies that produce appropriate treatment for each patient and kind of tumor. Therefore, identifying cellular and molecular components involved in the process of carcinogenesis for development of chemotherapeutic agents involved in restoration or selective destruction of cancer cells is necessary. Currently, it has been shown that certain drugs such as antibiotics (tetracycline, sulfonamide and b-lactams) and others chemicals compounds (quinoxalines) that are used for another purpose showed anticancer effects with antiproliferative and inhibitory activity. Therefore these could be a new option for pharmacological treatment of cancer. INTRODUCCIÓNLa célula es la unidad estructural y funcional de todo ser vivo, de la cual existen diferentes tipos; el cuerpo humano, por ejemplo, está compuesto por más de 200 tipos de células incomparables, cada una especializada para desarrollar funciones específicas. Las similitudes fundamentales de los diferentes tipos celulares proporcionan un marco común para estudiar los disímiles aspectos de la biología celular y molecular con distintas aplicaciones. El proceso más importante dentro de las células es su metabolismo, el cual se define como el conjunto de reacciones bioquímicas y procesos físico-químicos que ocurren dentro de ésta; estos procesos complejos están interrelacionados con la base de la vida a escala molecular, y permiten las diversas actividades celulares. El metabolismo se divide en dos procesos: catabolismo y anabolismo. Las reacciones catabólicas liberan energía, mientras que las anabólicas utilizan esta energía, por lo tanto, el catabolismo y el anabol...

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A Novel β-Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage

Cited by 71 publications

References 28 publications

Cytotoxicity and Enterotoxicity of the Thermostable Direct Hemolysin‐Deletion Mutants of Vibrio parahaemolyticus

Cytotoxicity and Enterotoxicity of the Thermostable Direct Hemolysin‐Deletion Mutants of Vibrio parahaemolyticus

Differentialin vitroinhibition effects of some antibiotics on tumor associated carbonic anhydrase isozymes of hCA-IX and hCA-XII

Cellular and molecular effect of antitumor agents

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