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

PLoS ONE

Volumn 8, Issue 5, 2013, Pages

  Mackenzie, Gerardo G ^a   Huang, Liqun ^a   Alston, Ninche ^a   Ouyang, Nengtai ^a,b   Vrankova, Kvetoslava ^a   Mattheolabakis, George ^a   Constantinides, Panayiotis P ^b   Rigas, Basil ^a  

^a STONY BROOK UNIVERSITY   (United States)

^b Medicon Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CIMETIDINE; MDC 1112; NEW DRUG; PROTEIN BCL XL; PROTEIN MCL 1; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; SURVIVIN; UNCLASSIFIED DRUG; VALPROIC ACID DERIVATIVE; ANTINEOPLASTIC AGENT; MDC-1112; ORGANOPHOSPHATE; STAT3 PROTEIN, HUMAN; VALPROIC ACID;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER GROWTH; CANCER INHIBITION; CELLULAR DISTRIBUTION; CONTROLLED STUDY; CYTOSOL; DRUG EFFICACY; DRUG POTENTIATION; DRUG TARGETING; GENE OVEREXPRESSION; HUMAN; HUMAN CELL; IC 50; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRION; MOUSE; NONHUMAN; PANCREAS CANCER; PROTEIN DEGRADATION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR XENOGRAFT; ANALOGS AND DERIVATIVES; ANIMAL; BAGG ALBINO MOUSE; DRUG EFFECTS; DRUG SCREENING; FEMALE; METABOLISM; MOLECULARLY TARGETED THERAPY; NUDE MOUSE; PANCREATIC NEOPLASMS; PATHOLOGY; PROTEIN TRANSPORT; TUMOR CELL LINE; TUMOR VOLUME;

ANIMALIA; MUS;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CIMETIDINE; DRUG SYNERGISM; FEMALE; HUMANS; MEMBRANE POTENTIAL, MITOCHONDRIAL; MICE; MICE, INBRED BALB C; MICE, NUDE; MITOCHONDRIA; MOLECULAR TARGETED THERAPY; ORGANOPHOSPHATES; PANCREATIC NEOPLASMS; PROTEIN TRANSPORT; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR; TUMOR BURDEN; VALPROIC ACID; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84877055764     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0061532     Document Type: Article

References (31)

1. Jemal A, Siegel R, Xu J, Ward E, (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.
2. Fukuda A, Wang SC, Morris JPt, Folias AE, Liou A, et al. (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19: 441-455.
3. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, et al. (2011) Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19: 456-469.
4. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, et al. (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324: 1713-1716.
5. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, et al. (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323: 793-797.
6. Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, et al. (2003) Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 125: 891-905.
7. Sahu RP, Srivastava SK, (2009) The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst 101: 176-193.
8. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, et al. (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276: 36734-36741.
9. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, et al. (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20: 6969-6978.
10. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, et al. (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22: 3411-3420.
11. Tan J, Cang S, Ma Y, Petrillo RL, Liu D, (2010) Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 3: 5.
12. Naito A, Carcel-Trullols J, Xie CH, Evans TT, Mizumachi T, et al. (2008) Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line. Int J Cancer 122: 1506-1511.
13. Zhao W, Mackenzie GG, Murray OT, Zhang Z, Rigas B, (2009) Phosphoaspirin (MDC-43), a novel benzyl ester of aspirin, inhibits the growth of human cancer cell lines more potently than aspirin: a redox-dependent effect. Carcinogenesis 30: 512-519.
14. Mackenzie GG, Sun Y, Huang L, Xie G, Ouyang N, et al. (2010) Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology 139: 1320-1332.
15. Barksdale KA, Bijur GN, (2009) The basal flux of Akt in the mitochondria is mediated by heat shock protein 90. J Neurochem 108: 1289-1299.
16. Wen Z, Darnell JE Jr, (1997) Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res 25: 2062-2067.
17. Szczepanek K, Chen Q, Derecka M, Salloum FN, Zhang Q, et al. (2011) Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species. J Biol Chem 286: 29610-29620.
18. Mackenzie GG, Ouyang N, Xie G, Vrankova K, Huang L, et al. (2011) Phospho-sulindac (OXT-328) combined with difluoromethylornithine prevents colon cancer in mice. Cancer Prev Res (Phila) 4: 1052-1060.
19. Mamon HJ, Niedzwiecki D, Hollis D, Tan BR, Mayer RJ, et al. (2011) A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma: cancer and Leukemia Group B (CALGB) 80003. Cancer 117: 2620-2628.
20. Schuller HM, Al-Wadei HA, Majidi M, (2008) GABA B receptor is a novel drug target for pancreatic cancer. Cancer 112: 767-778.
21. Surucu O, Middeke M, Hoschele I, Kalder J, Hennig S, et al. (2004) Tumour growth inhibition of human pancreatic cancer xenografts in SCID mice by cimetidine. Inflamm Res 53Suppl 1: S39-40.
22. Wang W, Adachi M, Zhang R, Zhou J, Zhu D, (2009) A novel combination therapy with arsenic trioxide and parthenolide against pancreatic cancer cells. Pancreas 38: e114-123.
23. Zhang Z, Rigas B, (2006) NF-kappaB, inflammation and pancreatic carcinogenesis: NF-kappaB as a chemoprevention target (review). Int J Oncol 29: 185-192.
24. Sclabas GM, Fujioka S, Schmidt C, Evans DB, Chiao PJ, (2003) NF-kappaB in pancreatic cancer. Int J Gastrointest Cancer 33: 15-26.
25. Algul H, Adler G, Schmid RM, (2002) NF-kappaB/Rel transcriptional pathway: implications in pancreatic cancer. Int J Gastrointest Cancer 31: 71-78.
26. Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, et al. (2007) Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1alpha autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 13: 6459-6468.
27. Yamamoto H, Itoh N, Kawano S, Yatsukawa Y, Momose T, et al. (2011) Dual role of the receptor Tom20 in specificity and efficiency of protein import into mitochondria. Proc Natl Acad Sci U S A 108: 91-96.
28. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R, (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105: 771-785.
29. Kashfi K, Rigas B, (2007) The mechanism of action of nitric oxide-donating aspirin. Biochem Biophys Res Commun 358: 1096-1101.
30. Buettner R, Corzano R, Rashid R, Lin J, Senthil M, et al. (2011) Alkylation of cysteine 468 in Stat3 defines a novel site for therapeutic development. ACS Chem Biol 6: 432-443.
31. Sarafian TA, Montes C, Imura T, Qi J, Coppola G, et al. (2010) Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PLoS One 5: e9532.