Minor grove binding ligands disrupt PARP-1 activation pathways

Кирсанов, Кирилл И.; Kotova, Elena; Makhov, Petr; Golovine, Konstantin; Lesovaya, Ekaterina A.; Kolenko, Vladimir; Yakubovskaya, Marianna G.; Tulin, Adrian

doi:10.18632/oncotarget.1742

Cited by 27 publications

(19 citation statements)

References 46 publications

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“…The PNX0010 human ccRCC cell line (Kirsanov et al , 2014) was a kind gift of Dr Vladimir Khazak (Priaxon Inc.). The HUVEC cell line was obtained from ATCC.…”

Section: Methodsmentioning

confidence: 99%

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

et al. 2017

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Background:Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.Methods:We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.Results:The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.Conclusions:The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

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“…The PNX0010 human ccRCC cell line (Kirsanov et al , 2014) was a kind gift of Dr Vladimir Khazak (Priaxon Inc.). The HUVEC cell line was obtained from ATCC.…”

Section: Methodsmentioning

confidence: 99%

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

et al. 2017

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“…Previously, we found that breast (BT474), prostate (PC3), and kidney (PNX0010) cancer cells show an unusually high level of PARP-1 activity (Kirsanov et al, 2014). Therefore, we used these cell lines to test the efficacy of PARP-1 inhibition by new and classical inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…To accomplish this, we employed a blind screen of a random small- molecule collection containing 50,000 compounds. As noted above, PARP-1 can be regulated by competing for binding with NAD (D'Amours et al, 1999), as well as by two additional routes: obstruction of PARP-1 binding with DNA (Kirsanov et al, 2014) and disruption of PARP-1 interaction with histone H4 (Pinnola et al, 2007). The latter rout of activation is highly specific to PARP-1.…”

Section: Introductionmentioning

confidence: 99%

Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo

Thomas

Lodhi

et al. 2016

EBioMedicine

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The clinical potential of PARP-1 inhibitors has been recognized > 10 years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials.

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“…В настоящее время эффекты дестабилизации хроматина ДНК-тропными агентами были описаны лишь для нового противоопухолевого препарата CBL0137 [17,18] и ряда узкобороздочных лигандов (УБЛ) [19]. Причем при действии как CBL0137, так и УБЛ наблюдалось повышение уровня экспрессии ретротранспозонов и других повторяющихся последовательностей ДНК.…”

Section: Introductionunclassified

Activation of interferon-α signaling by resveratrol, genistein and quercetin

Vlasova¹,

Борунова²,

Safina³

et al. 2019

Sib. onkol. ž.

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Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon- interferon-α signaling.

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Minor grove binding ligands disrupt PARP-1 activation pathways

Cited by 27 publications

References 46 publications

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma

Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo

Activation of interferon-α signaling by resveratrol, genistein and quercetin

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