Phospho-valproic acid (MDC-1112) reduces pancreatic cancer growth in patient-derived tumor xenografts and KPC mice: enhanced efficacy when combined with gemcitabine.

Abstract

New chemotherapeutic agents are needed for pancreatic cancer (PC). We have previously shown that phospho-valproic acid (MDC-1112) is effective in cell-line xenografts of PC. Here, we explored whether MDC-1112 is effective in additional clinically relevant animal models of PC and whether MDC-1112 enhances the anticancer effect of clinically used chemotherapeutic agents. MDC-1112 alone strongly reduced patient-derived pancreatic tumor xenograft growth, and extended survival of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mice. In both models, MDC-1112 inhibited STAT3 activation and its downstream signals, including Bcl-xL and cyclin D1. In human PC cell lines, P-V enhanced the growth inhibitory effect of gemcitabine (GEM), Abraxane and 5-FU, but not that of irinotecan. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of MDC-1112/GEM combination. Furthermore, MDC-1112 enhanced GEM's effect on colony formation, apoptosis, cell migration, and cell invasion. In vivo, MDC-1112 and GEM, given alone, reduced patient-derived pancreatic tumor xenograft growth by 58% and 87%, respectively; whereas MDC-1112/GEM combination reduced tumor growth by 94%, inducing tumor stasis. In conclusion, MDC-1112 should be further explored as a potential agent to be used in combination with GEM for treating PC.

• Authors: Dingyuan Luo, Matthew G Digiovanni, Ran Wei, Joseph F Lacomb, Jennie L Williams, Basil Rigas, Gerardo G Mackenzie
• Journal: Carcinogenesis (Carcinogenesis) Vol. 41 Issue 7 Pg. 927-939 (07 14 2020) ISSN: 1460-2180 [Electronic] England
• PMID: 31584613 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• MDC-1112
• Organophosphates
• Deoxycytidine
• Valproic Acid
• Gemcitabine

Topics

• Abnormalities, Multiple (drug therapy, pathology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Humans
• Keratoconus (congenital, drug therapy, pathology)
• Mice
• Organophosphates (pharmacology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Signal Transduction (drug effects)
• Valproic Acid (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays
• Gemcitabine