scholarly journals Erratum to: The effect of chronic dosing and p53 status on the genotoxicity of pro-oxidant chemicals in vitro

Mutagenesis ◽  
2021 ◽  
Author(s):  
Emrah Dural ◽  
Ume-Kulsoom Shah ◽  
Demi Pritchard ◽  
Katherine Emma Chapman ◽  
Shareen Heather Doak ◽  
...  
Keyword(s):  
P53 Status

The effect of chronic dosing and p53 status on the genotoxicity of pro-oxidant chemicals in vitro

Mutagenesis ◽  
2020 ◽  
Author(s):  
Emrah Dural ◽  
Ume-Kulsoom Shah ◽  
Demi Pritchard ◽  
Katherine Emma Chapman ◽  
Shareen Heather Doak ◽  
...  
Keyword(s):  
Test Method ◽  
Dose Fractionation ◽  
Population Doubling ◽  
Relative Population ◽  
Dichlorofluorescein Diacetate ◽  
Ros Formation ◽  
P53 Status ◽  
Tk6 Cells ◽  
Unique Mechanism

Abstract In this study, we have studied the cytotoxicity and genotoxic potency of 3 pro-oxidants; H2O2, menadione and KBrO3 in different dosing scenarios, namely acute (1-day dosing) and chronic (5-days). For this purpose, relative population doubling (RPD%) and mononucleated micronucleus (MN) test were used. TK6 cells and NH32 were employed in in vitro experiments. In the study, the total acute dose was divided into 5 days for each prooxidant chemicals by dose fractionation (1/5th per day) method. Acute dosing was compared to chronic dosing. The oxidative stress caused by the exposure of cells with pro-oxidant chemicals to the cells was determined by an optimized 2′,7′-dichlorofluorescein diacetate (DCFHDA) test method. The antioxidant levels of the cell lines were altered with buthionine sulfoxide (BSO) and N-acetyl cysteine (NAC), and the effect of antioxidant capacity on the MN formation in the cells was observed with this method. In the case of H2O2 and menadione, fractional dosing has been observed to result in lower toxicity and lower genotoxicity. But in the case of KBrO3, unlike the other 2 pro-oxidants, higher MN induction was observed with fractionated doses. DCFHDA test clearly demonstrated ROS induction with H2O2 and menadione but not with KBrO3. Unexpectedly, DCFHDA test demonstrated that KBrO3 did not cause an increase ROS levels in both acute and chronic dosing, suggesting an alternative ROS induction mechanism. It was also observed that, treatment with BSO and NAC, caused increasing and decreasing of MN fold change respectively, allowing further ROS specific mechanisms to be explored. Hence, dose fractionation expectedly caused less MN, cytotoxicity and ROS formation with H2O2 and menadione exposure, but not with KBrO3. This implies a unique mechanism of action for KBrO3 induced genotoxicity. Chronic dosing in vitro may be a valuable approach allowing better understanding of how chemicals damage DNA and pose human hazards.

scholarly journals SB225002 Promotes Mitotic Catastrophe in Chemo-Sensitive and -Resistant Ovarian Cancer Cells Independent of p53 Status In Vitro

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e54572 ◽  
Author(s):  
Meirong Du ◽  
Qing Qiu ◽  
Andree Gruslin ◽  
John Gordon ◽  
Miao He ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Mitotic Catastrophe ◽  
Ovarian Cancer Cells ◽  
P53 Status

Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2510-2510
Author(s):  
Gaël Roué ◽  
Mónica López-Guerra ◽  
Pierre Milpied ◽  
Patricia Pérez-Galán ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Mantle Cell ◽  
P53 Status

Abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.

scholarly journals Combination of BCL-2 Inhibition and Triptolide Causes Synthetic Lethality in Acute Myeloid Leukemia through Preventing Reciprocal Resistance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2083-2083
Author(s):  
Bing Xu ◽  
Yuanfei Shi ◽  
Long Liu ◽  
Bing Z Carter
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Synthetic Lethality ◽  
Leukemic Cells ◽  
Apoptotic Pathway ◽  
P53 Status ◽  
Acute Myeloid

BCL-2 inhibition exerts effective pro-apoptotic activities in acute myeloid leukemia (AML) but clinical efficacy as a monotherapy was limited in part due to the treatment-induced MCL-1 increase. Triptolide (TPL) exhibits anti-tumor activities in part by upregulating pro-apoptotic BCL-2 proteins and decreasing MCL-1 expression in various malignant cells. We hypothesized that combined BCL-2 inhibition and TPL exert synergistic anti-leukemia activities and prevent the resistance to BCL-2 inhibition in AML. We here report that TPL combined with BCL-2 inhibitor ABT-199 synergistically induced apoptosis in leukemic cells regardless of p53 status through activating the intrinsic mitochondrial apoptotic pathway in vitro. Although ABT-199 or TPL alone inhibited AML growth in vivo, the combination therapy demonstrated a significantly stronger anti-leukemic effect. Mechanistically, TPL significantly upregulated BH3 only proteins including PUMA, NOXA, BID and BIM and decreased MCL-1 but upregulated BCL-2 expression in both p53 wild type and p53 mutant AML cell lines, while the combination decreased both BCL-2 and MCL-1 and further increased BH3 only BCL-2 proteins. MCL-1 and BCL-2 increases associated with respective ABT-199 and TPL treatment and resistance were also observed in vivo. Significantly downregulating MCL-1 and elevating BH3 only proteins by TPL could not only potentially block MCL-1-mediated resistance but also enhance anti-leukemic efficacy of ABT-199. Conversely, BCL-2 inhibition counteracted the potential resistance of TPL mediated by upregulation of BCL-2. The combination further amplified the effect, which likely contributed to the synthetic lethality. This mutual blockade of potential resistance provides a rational basis for the promising clinical application of TPL and BCL-2 inhibition in AML independent of p53 status. Disclosures Carter: Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding.

In vitro sensitivity of colon tumor cells to 5 fluoro-uracile (5 FU), oxaliplatin and irinotecan: Role of microsatellite instability and p53 status

2003 ◽  
Vol 124 (4) ◽  
pp. A238
Author(s):  
Beatrice Parmentier ◽  
Jacques Abello ◽  
Catherine Bohas ◽  
Jean-Alain Chayvialle ◽  
Jean-Christophe Saurin
Keyword(s):  
Microsatellite Instability ◽  
Tumor Cells ◽  
Colon Tumor ◽  
In Vitro Sensitivity ◽  
P53 Status

scholarly journals hSirT1-Dependent Regulation of the PCAF-E2F1-p73 Apoptotic Pathway in Response to DNA Damage

2009 ◽  
Vol 29 (8) ◽  
pp. 1989-1998 ◽  
Author(s):  
Natalia Pediconi ◽  
Francesca Guerrieri ◽  
Stefania Vossio ◽  
Tiziana Bruno ◽  
Laura Belloni ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Stress Responses ◽  
Promoter Activity ◽  
Redox State ◽  
Apoptotic Pathway ◽  
Nadh Ratio ◽  
P53 Status

ABSTRACT The NAD+-dependent histone deacetylase hSirT1 regulates cell survival and stress responses by inhibiting p53-, NF-κB-, and E2F1-dependent transcription. Here we show that the hSirT1/PCAF interaction controls the E2F1/p73 apoptotic pathway. hSirT1 represses E2F1-dependent P1p73 promoter activity in untreated cells and inhibits its activation in response to DNA damage. hSirT1, PCAF, and E2F1 are corecruited in vivo on theP1p73 promoter. hSirT1 deacetylates PCAF in vitro and modulates PCAF acetylation in vivo. In cells exposed to apoptotic DNA damage, nuclear NAD+ levels decrease and inactivate hSirT1 without altering the hSirT1 interaction with PCAF and hSirT1 binding to the P1p73 promoter. The reactivation of hSirT1 by pyruvate that increases the [NAD+]/[NADH] ratio completely abolished the DNA damage-induced activation of TAp73 expression, thus linking the modulation of chromatin-bound hSirT1 deacetylase activity by the intracellular redox state with P1p73 promoter activity. The release of PCAF from hSirT1 repression favors the assembly of transcriptionally active PCAF/E2F1 complexes onto the P1p73 promoter and p53-independent apoptosis. Our results identify hSirT1 and PCAF as potential targets to modulate tumor cell survival and chemoresistance irrespective of p53 status.

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