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.

Mitochondrial Localized Stat3 Promotes Breast Cancer Growth via Phosphorylation of Serine 727

“…These studies suggest that there is a completely novel function of Stat3 governed by its presence in the mitochondria where it controls energy balance. Subsequent studies have confirmed and extended these initial observations in a variety of non-transformed cells (3)(4)(5)(6)(7)(8) and in the growth of pancreatic cancer cells in mice (9).…”

“…Constitutive serine phosphorylation of Stat3 has been observed in many human tumors and can be present in the absence of the protein being tyrosinephosphorylated (11). Results from the laboratory of Farrar et al (12) implicated serine 727 as being important for prostate cancer growth and recent studies implicate mitoStat3 in the growth of pancreatic cancer (9). We chose to examine the effects of mitoStat3 in 4T1 cells because expression of Stat3 is required for these cells to form tumors in immunocompetent mice (22).…”

Synergistic effect of cytokine-induced killer cell with valproate inhibits growth of hepatocellular carcinoma cell in a mouse model

“…In previous studies, 10 mg/kg and 30 mg/kg were selected as minimum VPA doses. 25,26 VPA treatment was started when tumors had grown to a palpable size (0.2 cm 3 ). VPA was dissolved in distilled water and injected into the peritoneum of 10 mice once daily at a dose of 10 (n D 5) or 30 (n D 5) mg/kg/day for 7 d. The control group was injected with solvent (n D 5).…”

Chloroquine and Valproic Acid Combined Treatment in Vitro has Enhanced Cytotoxicity in an Osteosarcoma Cell Line

“…Chuan-Kun Wang*, Xi-Dong Yu, Qiang Li, Gang Xie, Yue Teng broad spectrum of cancer cells (Shan et al, 2012;Sidana et al, 2012;Jasek et al, 2012;Kwiecińska et al, 2012;Mackenzie et al, 2013) through the increase histone acetylation and apoptosis related gene expression activation, but the detailed mechanisms are still not clearly (Kwiecińska et al, 2011;Xie et al, 2012;McCormack et al, 2013;Nie et al, 2013).…”