Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice

Gerardo Mackenzie, Liqun Huang, Ninche Alston, Nengtai Ouyang, Kvetoslava Vrankova, George Mattheolabakis, Panayiotis P. Constantinides, Basil Rigas

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

Original languageEnglish (US)
Article numbere61532
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 1 2013
Externally publishedYes

Fingerprint

valproic acid
pancreatic neoplasms
Phosphorylation
Valproic Acid
Pancreatic Neoplasms
Mitochondria
Cimetidine
mice
Growth
Heterografts
Tumors
Reactive Oxygen Species
phosphorylation
Animals
Association reactions
Apoptosis
cimetidine
Derivatives
STAT3 Transcription Factor
human growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice. / Mackenzie, Gerardo; Huang, Liqun; Alston, Ninche; Ouyang, Nengtai; Vrankova, Kvetoslava; Mattheolabakis, George; Constantinides, Panayiotis P.; Rigas, Basil.

In: PLoS One, Vol. 8, No. 5, e61532, 01.05.2013.

Research output: Contribution to journalArticle

Mackenzie, G, Huang, L, Alston, N, Ouyang, N, Vrankova, K, Mattheolabakis, G, Constantinides, PP & Rigas, B 2013, 'Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice', PLoS One, vol. 8, no. 5, e61532. https://doi.org/10.1371/journal.pone.0061532
Mackenzie, Gerardo ; Huang, Liqun ; Alston, Ninche ; Ouyang, Nengtai ; Vrankova, Kvetoslava ; Mattheolabakis, George ; Constantinides, Panayiotis P. ; Rigas, Basil. / Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice. In: PLoS One. 2013 ; Vol. 8, No. 5.
@article{2b0a5b1d3e334a8591f20126f9ae1655,
title = "Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice",
abstract = "New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60{\%}-97{\%}, and 100{\%} when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.",
author = "Gerardo Mackenzie and Liqun Huang and Ninche Alston and Nengtai Ouyang and Kvetoslava Vrankova and George Mattheolabakis and Constantinides, {Panayiotis P.} and Basil Rigas",
year = "2013",
month = "5",
day = "1",
doi = "10.1371/journal.pone.0061532",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Targeting Mitochondrial STAT3 with the Novel Phospho-Valproic Acid (MDC-1112) Inhibits Pancreatic Cancer Growth in Mice

AU - Mackenzie, Gerardo

AU - Huang, Liqun

AU - Alston, Ninche

AU - Ouyang, Nengtai

AU - Vrankova, Kvetoslava

AU - Mattheolabakis, George

AU - Constantinides, Panayiotis P.

AU - Rigas, Basil

PY - 2013/5/1

Y1 - 2013/5/1

N2 - New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

AB - New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

UR - http://www.scopus.com/inward/record.url?scp=84877055764&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877055764&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0061532

DO - 10.1371/journal.pone.0061532

M3 - Article

C2 - 23650499

AN - SCOPUS:84877055764

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e61532

ER -