Oncotarget: ATM inhibition overcomes resistance to histone deacetylase inhibitor


The cover for

issue 37

of Oncotarget features Figure 7, ”


The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL,


” by Scotto, et al. which reported that the antiproliferative effect induced by histone deactylase inhibitors is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug.

HDAC inhibitors appear to activate p21 expression via

ataxia


telangiectasia

mutated activity.

The

Oncotarget

authors explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor.

KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase.

Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor.

Dr. Owen A. O’Connor from

The Columbia University Medical Center

said, ”

HDAC inhibitors (HDACi) have emerged as valuable drugs in the treatment of select

lymphomas

and synergize with a diverse range of pharmacological and biological agents.

The observation leads to the following hypothesis:

if induction of p21 compromises the efficacy of HDAC inhibitors, then strategies to mitigate HDAC inhibitor induced p21 expression could lead to promising synergistic combinations

.

Induction of p21 by HDAC inhibitors is compromised in A-T cells given that ATM activity is essential for HDAC inhibitor-induced p21 expression.

Collectively, these observations have led to the following hypothesis:

If ATM activity is necessary for HDAC inhibitor mediated p21 induction, then selective ATM inhibitors could mitigate the HDAC induced p21 expression and potentiate its cytotoxic effect

.

The ATM inhibitor nullifies HDAC induction of p21 expression resulting in a synergistic interaction.

KU60019 reduces p21 expression at the transcriptional level and antagonizes romidepsin transcriptional induction of p21. In both instances, the result is a markedly down-regulation of p21 expression at the protein level.

The O’Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival.

Strategies directed toward understanding how to mitigate the unfavorable influences of the class can lead to improved efficacy in rational combinations.

Many examples of drug synergy with HDAC inhibitors have been driven by random efforts in mixing and matching in order to identify possible complementary partners.

Obviously, a clear understanding of the molecular pharmacologic features of pleotropic drug classes like HDAC inhibitors can afford unique opportunities to think about logical combinations.

Ultimately, these approaches need to be translated to the clinic in order to establish therapeutic merit in the clinic.


Sign up for free Altmetric alerts about this article


DOI



https:/

/

doi.

org/

10.

18632/

oncotarget.

27723


Full text



https:/

/

www.

oncotarget.

com/

article/

27723/

text/


Correspondence to

– Owen A. O’Connor –

owenaoconnor@gmail.com


Keywords




lymphoma

,

HDAC inhibitor

,

ATM inhibitor

,

p21

,

cell cycle



About Oncotarget


Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.


To learn more about Oncotarget, please visit

https:/

/

www.

oncotarget.

com

or connect with:


SoundCloud –


https:/

/

soundcloud.

com/

oncotarget



Facebook –


https:/

/

www.

facebook.

com/

Oncotarget/




Twitter –


https:/

/

twitter.

com/

oncotarget



LinkedIn –


https:/

/

www.

linkedin.

com/

company/

oncotarget



Pinterest –


https:/

/

www.

pinterest.

com/

oncotarget/




Reddit –


https:/

/

www.

reddit.

com/

user/

Oncotarget/


Oncotarget is published by Impact Journals, LLC please visit

http://www.

ImpactJournals.

com

or connect with

@ImpactJrnls


Media Contact



MEDIA@IMPACTJOURNALS.COM



18009220957×105

Copyright © 2020 Impact Journals, LLC

Impact Journals is a registered trademark of Impact Journals, LLC

This part of information is sourced from https://www.eurekalert.org/pub_releases/2020-09/ijl-oai091620.php