A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy

Komarov, Pavel G.; Komarova, Elena A.; Kondratov, Roman V.; Christov-Tselkov, Konstantin; Coon, John S.; Chernov, Mikhail V.; Gudkov, Andrei V.

doi:10.1126/science.285.5434.1733

Cited by 1,155 publications

(967 citation statements)

References 26 publications

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“…36 On the other hand, vanadate may be useful for inhibiting DNA damage-induced apoptosis, as a radioprotector, or for inhibiting the side effects of cancer therapy. Several researchers have identified chemical inhibitors of p53, such as pifithrin, 37 cadmium, 24,33 and salicylate. 38 Among these inhibitors, pifithrin inhibits the nuclear localization of p53 after DNA damage, but cadmium and salicylate inhibit the DNAbinding activity of p53.…”

Section: Discussionmentioning

confidence: 99%

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

et al. 2005

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We previously reported that p42/SETb is a substrate for caspase-7 in irradiated MOLT-4 cells, and that treating the cells with sodium orthovanadate (vanadate) inhibits p42/SETb's caspase-mediated cleavage. Here, we initially found that the inhibitory effect of vanadate was due to the suppression of caspase activation but not of caspase activity. Further investigations revealed that vanadate suppressed upstream of apoptotic events, such as the loss of mitochondrial membrane potential, the conformational change of Bax, and p53 transactivation, although the accumulation, total phosphorylation, and phosphorylation of six individual sites of p53 were not affected. Importantly, vanadate suppressed p53-dependent apoptosis, but not p53-independent apoptosis. Finally, gel-shift and chromatin immunoprecipitation assays conclusively demonstrated that vanadate inhibits the DNA-binding activity of p53. Vanadate is conventionally used as an inhibitor of protein tyrosine phosphatases (PTPs); however, we recommend that the influence of vanadate not only on PTPs but also on p53 be considered before using it.

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Section: Discussionmentioning

confidence: 99%

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

et al. 2005

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“…We used the following compounds to modulate aminoglycoside-induced hair cell death: the Bax channel blocker (±)-1-(3,6-dibromocarbazol-9-yl)-3-piperazin-1-yl-propan-2-ol, bis TFA (Bombrun et al 2003), the p53 inhibitors pifithrin-α (PFTα) (Komarov et al 1999;Endo et al 2006) and pifithrin-μ (PFTμ) (Strom et al 2006), and the Mdm2 inhibitor nutlin-3a (Vassilev et al 2004). All inhibitors were purchased from EMD Millipore (Darmstadt, Germany) and dissolved in DMSO.…”

Section: Drug Treatmentsmentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

112

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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“…Selective inhibitors for p53 (α-PFT, α-pifithrin) [21], Erk (PD98059, 2′-amino-3′-methoxyflavone) [22] [22], and c-Jun NH 2 -terminal kinase or JNK (SP600125, 1,9-pyrazoloanthrone) [22] were purchased from Calbiochem (San Diego, CA). BU, N-acetylcysteine (NAC) and 5-bromo-2′-deoxyuridine (BrdU) were obtained from Sigma (St. Louis, MO).…”

Section: Reagentsmentioning

confidence: 99%

“…To further clarify the roles of the p53 pathway and the Erk-p38 MAPK cascade in BU-induced senescence, WI38 cells were pre-treated with α-PFT, PD98059, SB203580, and SP600125 prior to BU treatment to specifically inhibit p53, Erk, p38, and JNK, respectively [21,22]. The induction of senescence in WI38 cells by BU was analyzed by quantification of SA-β-gal staining and BrdU incorporation.…”

Section: Bu Induces Wi38 Cell Senescence Via the Erk-p38 Mapk Pathwaymentioning

confidence: 99%

Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

Probin

Wang

Zhou

2007

Free Radical Biology and Medicine

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Induction of cellular senescence is a common response of a normal cell to a DNA damaging agent, which may contribute to cancer chemotherapy-and ionizing radiation-induced normal tissue injury. The induction has been largely attributed to the activation of p53. However, the results from the present study suggest that busulfan (BU), an alkylating agent that causes DNA damage by crosslinking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. The induction of WI38 cell senescence is initiated by a transient depletion of intracellular glutathione (GSH) and followed by a continuous increase in reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the activation of the Erk and p38 MAPK pathway. Incubation of WI38 cells with N-acetyl-cysteine (NAC) replenishes intracellular GSH; abrogates the increased production of ROS; ameliorates Erk and p38 MAPK activation; and attenuates senescence induction by BU. Thus, inhibition of senescence induction using a potent antioxidant or specific inhibitor of the Erk and p38 MAPK pathway has the potential to be developed as a mechanism-based strategy to ameliorate cancer therapy-induced normal tissue damage.

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A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy

Cited by 1,155 publications

References 26 publications

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis by inactivating p53

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

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