TY - JOUR
T1 - The histone deacetylase inhibitor M344 as a multifaceted therapy for pancreatic cancer
AU - Knoche, Shelby M.
AU - Brumfield, Gabrielle L.
AU - Goetz, Benjamin T.
AU - Sliker, Bailee H.
AU - Larson, Alaina C.
AU - Olson, Madeline T.
AU - Poelaert, Brittany J.
AU - Bavari, Audrey
AU - Yan, Ying
AU - Black, Jennifer D.
AU - Solheim, Joyce C.
N1 - Funding Information:
This work was supported by National Institutes of Health (www.nih.gov) grants P30 CA036727 (Pilot Grant to JS), T32 CA009476 (JB; Fellowships to BS, MO, and AL), U54 GM115458 (Pilot Grant to JS), R25 CA221777 (Fellowship to AB), P30 GM127200 (Core Facilities Voucher to JS), the State of Nebraska (www.nebraska.gov) (funding to JS), and the UNMC Graduate Studies Office Fellowship Program (www.unmc.edu/ gradstudies) (BP and SK). The UNMC Flow Cytometry Research Facility is supported through the Office of the Vice Chancellor for Research (www.unmc.edu/vcr/), the Nebraska Research Initiative (nebraska.edu/offices-policies/provostsoffice/research/nebraska-research-initiative), the Fred & Pamela Buffett Cancer Center (www.unmc. edu/cancercenter/), the University of Nebraska Foundation (nufoundation.org), the Nebraska Bankers Association Fund (www.nebankers.org), and the National Institutes of Health Shared Instrument Grant Program (orip.nih.gov). The Small Animal Ultrasound Core Facility receives support from the Office of Vice Chancellor for Research (www.unmc.edu/vcr/), the Fred & Pamela Buffett Cancer Center (www.unmc.edu/ cancercenter/), and the Nebraska Center for Nanomedicine (P30 GM127200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Michael A. (Tony) Hollingsworth and Dr. Amarnath Natarajan for cell lines and Dr. Ted Hansen for hybridomas. We also thank the UNMC Molecular Core Facility and Dr. Prakash Radhakrishnan for providing access to the absorbance readers, and we thank the personnel of the UNMC Flow Cytometry Facility and Small Animal Ultrasound Core Facility for their assistance in this project.
Publisher Copyright:
© 2022 Knoche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022/9
Y1 - 2022/9
N2 - The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.
AB - The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.
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U2 - 10.1371/journal.pone.0273518
DO - 10.1371/journal.pone.0273518
M3 - Article
C2 - 36126055
AN - SCOPUS:85138191042
SN - 1932-6203
VL - 17
JO - PloS one
JF - PloS one
IS - 9 September
M1 - e0273518
ER -