Hydrogen Peroxide Causes RAD9-dependent Cell Cycle Arrest in G2 in Saccharomyces cerevisiae whereas Menadione Causes G1 Arrest Independent of RAD9 Function

Flattery-O'Brien, Jacinta; Dawes, Ian W.

doi:10.1074/jbc.273.15.8564

Cited by 101 publications

(40 citation statements)

References 44 publications

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“…This hypothesis was experimentally verified by first measuring ROS production (i) in the complete parasitic cell with a dichlorofluorescein diacetate-based assay and (ii) in the mitochondria with MitoSOX red in both WTM and resistant lines (61). A different response toward these two ROS-inducing compounds was also described in Saccharomyces cerevisiae (62). Among the drugs used here, three of them (AmB, Sb, and MIL) are reported to trigger ALCD associated with ROS in susceptible lines (46); furthermore, parasites showing single resistance to these drugs were shown to be tolerant to ALCD, a known trigger of oxidative stress (46).…”

Section: Discussionmentioning

confidence: 99%

Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations

Berg

García-Hernández

Cuypers

et al. 2015

Antimicrob Agents Chemother

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f Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.

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Section: Discussionmentioning

confidence: 99%

Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations

Berg

García-Hernández

Cuypers

et al. 2015

Antimicrob Agents Chemother

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“…Similar to oxidant agents, APDI can promote a temporary cell growth arrest in different phases of the cell cycle (25,28,29). This inhibition of proliferation can be caused by different mechanisms: the slowdown of cellular metabolism caused by a reduction of nutrient uptake, or the impaired bioenergetic function of mitochondria, via a direct signal generated in mitochondria related to growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Photodynamic Inactivation Inhibits Candida albicans Virulence Factors and Reduces In Vivo Pathogenicity

Kato

Prates

Sabino

et al. 2013

Antimicrob Agents Chemother

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The objective of this study was to evaluate whether Candida albicans exhibits altered pathogenicity characteristics following sublethal antimicrobial photodynamic inactivation (APDI) and if such alterations are maintained in the daughter cells. C. albicans was exposed to sublethal APDI by using methylene blue (MB) as a photosensitizer (0.05 mM) combined with a GaAlAs diode laser ( 660 nm, 75 mW/cm 2 , 9 to 27 J/cm 2 ). In vitro, we evaluated APDI effects on C. albicans growth, germ tube formation, sensitivity to oxidative and osmotic stress, cell wall integrity, and fluconazole susceptibility. In vivo, we evaluated C. albicans pathogenicity with a mouse model of systemic infection. Animal survival was evaluated daily. Sublethal MB-mediated APDI reduced the growth rate and the ability of C. albicans to form germ tubes compared to untreated cells (P < 0.05). Survival of mice systemically infected with C. albicans pretreated with APDI was significantly increased compared to mice infected with untreated yeast (P < 0.05). APDI increased C. albicans sensitivity to sodium dodecyl sulfate, caffeine, and hydrogen peroxide. The MIC for fluconazole for C. albicans was also reduced following sublethal MB-mediated APDI. However, none of those pathogenic parameters was altered in daughter cells of C. albicans submitted to APDI. These data suggest that APDI may inhibit virulence factors and reduce in vivo pathogenicity of C. albicans. The absence of alterations in daughter cells indicates that APDI effects are transitory. The MIC reduction for fluconazole following APDI suggests that this antifungal could be combined with APDI to treat C. albicans infections. Management of infections caused by clinically relevant fungal pathogens is a challenge due to the incidence of resistance that can develop during therapy, especially in immunocompromised individuals (1). The increasing need for prolonged use of antifungal drugs, longer than usually recommended for antibiotics, is accompanied by a corresponding increased incidence of side effects. Furthermore, the limited number of available antifungal compounds and the need to determine the susceptibility profile of the organism also complicate the treatment of these infections (2).The fungal species Candida albicans is part of the commensal flora of the human gastrointestinal and genitourinary tracts and can cause superficial infections of the mucosa and skin (3, 4). The infection depends on imbalances between increased C. albicans virulence attributes and impaired host defense systems. In immunocompromised individuals, however, C. albicans may invade deeper tissues, penetrate the blood vessels, and cause life-threatening systemic infections (3, 5).Photodynamic therapy (PDT) is a light-based treatment platform that is under development for several applications in oncology, dermatology, and ophthalmology, and it has recently been investigated as an antimicrobial therapy. The combination of nontoxic dyes referred to as photosensitizers (PS) and harmless low-intensity visible light generate...

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“…In particular, growth arrest always occurs in the G 1 phase before "Start" (Lee et al 1996;Wanke et al 1999;Belli et al 2001). The only exception to this is treatment that interferes with replication of DNA or nuclear division, resulting in G 2 arrest or arrest during mitosis (Jamieson 1992;Flattery-O'Brien and Dawes 1998).…”

Section: Introductionmentioning

confidence: 98%

Effects of growth temperature upshift on cell cycle progression in Cryptococcus neoformans

2003

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Cell cycle progression of Cryptococcus neoformans was studied for cells grown exponentially at 15°, 24°, and 30°C. Except for speed, cell cycle progression was similar. In particular, budding occurred relatively soon after initiation of DNA synthesis at 15°, 24°, and 30°C. After growth temperature was shifted from 15° to 30°C, cells were transiently arrested before initiation of DNA synthesis. Thus, similar to Saccharomyces cerevisiae, "Start" was the main susceptible cell cycle controlling point in C. neoformans. However, after spontaneous release from arrest as above, cells were further arrested in the unbudded state. Thus, the timing of budding was delayed just before the G 2 phase, or even until after entering the G 2 phase, but it was also transient, and 5 h after the shift buds emerged relatively soon after initiation of DNA synthesis. Thus, C. neoformans cells can respond adaptively to mild stress by delaying budding. The existence of the second susceptible cell cycle control point, i.e., budding, appears to endow C. neoformans with a unique characteristic of stronger inhibition of multiplication than growth. A model of the C. neoformans cell cycle is also presented.

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Hydrogen Peroxide Causes RAD9-dependent Cell Cycle Arrest in G2 in Saccharomyces cerevisiae whereas Menadione Causes G1 Arrest Independent of RAD9 Function

Cited by 101 publications

References 44 publications

Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations

Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations

Antimicrobial Photodynamic Inactivation Inhibits Candida albicans Virulence Factors and Reduces In Vivo Pathogenicity

Effects of growth temperature upshift on cell cycle progression in Cryptococcus neoformans

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