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GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted i...

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Autores principales: Booth, Laurence, West, Cameron, Moore, Robert P., Von Hoff, Daniel, Dent, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754587/
https://www.ncbi.nlm.nih.gov/pubmed/35035775
http://dx.doi.org/10.18632/oncotarget.28177
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author Booth, Laurence
West, Cameron
Moore, Robert P.
Von Hoff, Daniel
Dent, Paul
author_facet Booth, Laurence
West, Cameron
Moore, Robert P.
Von Hoff, Daniel
Dent, Paul
author_sort Booth, Laurence
collection PubMed
description GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1–3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux.
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spelling pubmed-87545872022-01-14 GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells Booth, Laurence West, Cameron Moore, Robert P. Von Hoff, Daniel Dent, Paul Oncotarget Research Paper GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1–3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux. Impact Journals LLC 2022-01-11 /pmc/articles/PMC8754587/ /pubmed/35035775 http://dx.doi.org/10.18632/oncotarget.28177 Text en Copyright: © 2022 Booth et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Booth, Laurence
West, Cameron
Moore, Robert P.
Von Hoff, Daniel
Dent, Paul
GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title_full GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title_fullStr GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title_full_unstemmed GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title_short GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells
title_sort gz17-6.02 and palbociclib interact to kill er+ breast cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754587/
https://www.ncbi.nlm.nih.gov/pubmed/35035775
http://dx.doi.org/10.18632/oncotarget.28177
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