Epigenetic instability may alter cell state transitions and anticancer drug resistance.
Drug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that...
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:6c9e006cf9054e7b99c24469fa567e8f2021-12-02T19:58:01ZEpigenetic instability may alter cell state transitions and anticancer drug resistance.1553-734X1553-735810.1371/journal.pcbi.1009307https://doaj.org/article/6c9e006cf9054e7b99c24469fa567e8f2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009307https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Drug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models and an integrated stochastic-deterministic model referenced to brain tumors. The stochastic cell state models included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. When moderate epigenetic instability was implemented the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. The stochastic-deterministic model utilized the stochastic cell state model to drive the dynamics of the DNA repair enzyme, methylguanine-methyltransferase (MGMT), that repairs temozolomide (TMZ)-induced O6-methylguanine (O6mG) adducts. In the presence of epigenetic instability, the production of MGMT decreased that coincided with an increase of O6mG adducts following a multiple-dose regimen of TMZ. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance.Anshul SainiJames M GalloPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009307 (2021) |
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Biology (General) QH301-705.5 |
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Biology (General) QH301-705.5 Anshul Saini James M Gallo Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
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Drug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models and an integrated stochastic-deterministic model referenced to brain tumors. The stochastic cell state models included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. When moderate epigenetic instability was implemented the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. The stochastic-deterministic model utilized the stochastic cell state model to drive the dynamics of the DNA repair enzyme, methylguanine-methyltransferase (MGMT), that repairs temozolomide (TMZ)-induced O6-methylguanine (O6mG) adducts. In the presence of epigenetic instability, the production of MGMT decreased that coincided with an increase of O6mG adducts following a multiple-dose regimen of TMZ. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance. |
format |
article |
author |
Anshul Saini James M Gallo |
author_facet |
Anshul Saini James M Gallo |
author_sort |
Anshul Saini |
title |
Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
title_short |
Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
title_full |
Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
title_fullStr |
Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
title_full_unstemmed |
Epigenetic instability may alter cell state transitions and anticancer drug resistance. |
title_sort |
epigenetic instability may alter cell state transitions and anticancer drug resistance. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doaj.org/article/6c9e006cf9054e7b99c24469fa567e8f |
work_keys_str_mv |
AT anshulsaini epigeneticinstabilitymayaltercellstatetransitionsandanticancerdrugresistance AT jamesmgallo epigeneticinstabilitymayaltercellstatetransitionsandanticancerdrugresistance |
_version_ |
1718375781948719104 |