Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Die Highlights vom Kongress des American College of Cardiology 2024

Im April diskutierten die Herz-Kreislauf-Spezialisten aus der ganzen Welt auf dem  Kongress des American College of Cardiology (ACC) u.a. neue Therapieansätze bei akutem Myokardinfarkt, koronarer Herzerkrankung, kardiogenem Schock oder Aortenklappenstenose. In unserem Kongress-Dossier haben wir für Sie Berichte über die „Late-Breaking Trials“ und andere wichtige Studien zusammengestellt. 
Erweiterte Suche
Anmelden
nach oben
Cancer Chemotherapy and Pharmacology
Erschienen in: Cancer Chemotherapy and Pharmacology 3/2009

01.02.2009 | Original Article

Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas

verfasst von: Rafael B. Erlich, Danny Rickwood, William B. Coman, Nicholas A. Saunders, Alexander Guminski

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2009

Einloggen, um Zugang zu erhalten

Abstract

Purposes

Here we investigate if valproic acid (VA) can enhance the efficacy of commonly used therapies for head and neck squamous cell carcinomas (HNSCC) and the molecular mechanisms that may be related to its anticancer effects.

Methods

Proliferation and viability of distinct cell types subjected to VA treatment alone or in combination regimens were measured through BrdU incorporation and LDH release, respectively. Molecular markers compatible with histone deacetylase inhibitory activity of VA were assessed through western blots assays in lysates obtained from cultured cells and tumour biopsies.

Results

Treatment of all cell types with VA resulted in a dose-dependent increase in histone H3 acetylation and p21 expression, as well as dose-dependent cytostasis. In contrast, the cytotoxic response to VA was variable and did not correlate with cytostasis, histone acetylation or p21 induction. The variability in response to VA was also observed in tumour biopsy samples collected from patients prior to and following a 1 week oral course of VA. In addition, we found that a combination of a clinically achievable concentration of VA plus cisplatin caused a threefold to sevenfold increase in cisplatin cytotoxicity in vitro.

Conclusions

VA acts as a histone deacetylase inhibitor (HDI) in SCC cells and normal human keratinocytes (HKs), potentiates the cytotoxic effect of cisplatin in SCC cell lines and decreases the viability of SCC cells as opposed to HKs. Taken together, the results provide initial evidence that VA might be a valuable drug in the development of better therapeutic regimens for HNSCC.
Literatur
1.
Atmaca A, Al-Batran SE, Maurer A, Neumann A, Heinzel T, Hentsch B, Schwarz SE, Hovelmann S, Gottlicher M, Knuth A, Jager E (2007) Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 97:177–182PubMedCrossRef
2.
Blaheta RA, Cinatl J Jr (2002) Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev 22:492–511PubMedCrossRef
3.
Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr (2005) Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 25:383–397PubMedCrossRef
4.
Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedCrossRef
5.
Brinkmann H, Dahler AL, Popa C, Serewko MM, Parsons PG, Gabrielli BG, Burgess AJ, Saunders NA (2001) Histone hyperacetylation induced by histone deacetylase inhibitors is not sufficient to cause growth inhibition in human dermal fibroblasts. J Biol Chem 276:22491–22499PubMedCrossRef
6.
Burgess A, Ruefli A, Beamish H, Warrener R, Saunders N, Johnstone R, Gabrielli B (2004) Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 23:6693–6701PubMedCrossRef
7.
Burgess AJ, Pavey S, Warrener R, Hunter LJ, Piva TJ, Musgrove EA, Saunders N, Parsons PG, Gabrielli BG (2001) Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity. Mol Pharmacol 60:828–837PubMed
8.
Camphausen K, Cerna D, Scott T, Sproull M, Burgan WE, Cerra MA, Fine H, Tofilon PJ (2005) Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int J Cancer 114:380–386PubMedCrossRef
9.
Camphausen K, Tofilon PJ (2007) Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol 25:4051–4056PubMedCrossRef
10.
Chin D, Boyle GM, Porceddu S, Theile DR, Parsons PG, Coman WB (2006) Head and neck cancer: past, present and future. Expert Rev Anticancer Ther 6:1111–1118PubMedCrossRef
11.
Chung YL, Wang AJ, Yao LF (2004) Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther 3:317–325PubMed
12.
Cinatl J Jr, Kotchetkov R, Blaheta R, Driever PH, Vogel JU, Cinatl J (2002) Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha. Int J Oncol 20:97–106PubMed
13.
Decker J, Goldstein JC (1982) Risk factors in head and neck cancer. N Engl J Med 306:1151–1155PubMed
14.
Fanucchi M, Khuri FR (2004) Chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck. Semin Oncol 31:809–815PubMedCrossRef
15.
Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head and neck cancer. N Engl J Med 345:1890–1900PubMedCrossRef
16.
Gabrielli BG, Johnstone RW, Saunders NA (2002) Identifying molecular targets mediating the anticancer activity of histone deacetylase inhibitors: a work in progress. Curr Cancer Drug Targets 2:337–353PubMedCrossRef
17.
Gore SD, Carducci MA (2000) Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Expert Opin Investig Drugs 9:2923–2934PubMedCrossRef
18.
Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606PubMedCrossRef
19.
Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS (2004) Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 64:1079–1086PubMedCrossRef
20.
Hoffmann K, Brosch G, Loidl P, Jung M (2000) First non-radioactive assay for in vitro screening of histone deacetylase inhibitors. Pharmazie 55:601–606PubMed
21.
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics. CA Cancer J Clin 54:8–29PubMedCrossRef
22.
Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299PubMedCrossRef
23.
Jones SJ, Dicker AJ, Dahler AL, Saunders NA (1997) E2F as a regulator of keratinocyte proliferation: implications for skin tumor development. J Invest Dermatol 109:187–193PubMedCrossRef
24.
Kartalou M, Essigmann JM (2001) Mechanisms of resistance to cisplatin. Mutat Res 478:23–43PubMed
25.
Kostrouchova M, Kostrouch Z (2007) Valproic acid, a molecular lead to multiple regulatory pathways. Folia Biol (Praha) 53:37–49
26.
Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22:3411–3420PubMedCrossRef
27.
Levy RAF, Riggs K, Hachad H (2002) Valproic acid: chemistry, biotransformation and pharmacokinetics. In: Levy RMB, Perucca E (eds) Anti-epileptic drugs. Lippincot Williams and Wilkins, Philadelphia, pp 780–800
28.
Licitra L, Vermorken JB (2004) Is there still a role for neoadjuvant chemotherapy in head and neck cancer? Ann Oncol 15:7–11PubMedCrossRef
29.
Luo J, Su F, Chen D, Shiloh A, Gu W (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408:377–381PubMedCrossRef
30.
Mao L, Hong WK, Papadimitrakopoulou VA (2004) Focus on head and neck cancer. Cancer Cell 5:311–316PubMedCrossRef
31.
Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T (2000) Regulation of E2F1 activity by acetylation. EMBO J 19:662–671PubMedCrossRef
32.
Nusinzon I, Horvath CM (2003) Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc Natl Acad Sci USA 100:14742–14747PubMedCrossRef
33.
Perucca E (2002) Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 16:695–714PubMedCrossRef
34.
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741PubMedCrossRef
35.
Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG, Gabrielli BG (2000) Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 11:2069–2083PubMed
36.
Rikiishi H, Shinohara F, Sato T, Sato Y, Suzuki M, Echigo S (2007) Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. Int J Oncol 30:1181–1188PubMed
37.
Santini V, Gozzini A, Ferrari G (2007) Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr Drug Metab 8:383–393PubMedCrossRef
38.
Sato T, Suzuki M, Sato Y, Echigo S, Rikiishi H (2006) Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells. Int J Oncol 28:1233–1241PubMed
39.
Saunders N, Dicker A, Popa C, Jones S, Dahler A (1999) Histone deacetylase inhibitors as potential anti-skin cancer agents. Cancer Res 59:399–404PubMed
40.
Serewko MM, Popa C, Dahler AL, Smith L, Strutton GM, Coman W, Dicker AJ, Saunders NA (2002) Alterations in gene expression and activity during squamous cell carcinoma development. Cancer Res 62:3759–3765PubMed
41.
Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279PubMedCrossRef
42.
Snead OC 3rd, Miles MV (1985) Treatment of status epilepticus in children with rectal sodium valproate. J Pediatr 106:323–325PubMedCrossRef
43.
Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307–320PubMedCrossRef
44.
Warrener R, Beamish H, Burgess A, Waterhouse NJ, Giles N, Fairlie D, Gabrielli B (2003) Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J 17:1550–1552PubMed
45.
Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552PubMedCrossRef
46.
Yildirim E, Zhang Z, Uz T, Chen CQ, Manev R, Manev H (2003) Valproate administration to mice increases histone acetylation and 5-lipoxygenase content in the hippocampus. Neurosci Lett 345:141–143PubMedCrossRef
47.
Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307:269–273PubMedCrossRef
Metadaten
Titel
Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas
verfasst von
Rafael B. Erlich
Danny Rickwood
William B. Coman
Nicholas A. Saunders
Alexander Guminski
Publikationsdatum
01.02.2009
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 3/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0747-1

Weitere Artikel der Ausgabe 3/2009

Cancer Chemotherapy and Pharmacology 3/2009 Zur Ausgabe

Letter to the Editor

Pharmacokinetic profile of imatinib mesylate and N-desmethyl-imatinib (CGP 74588) in children with newly diagnosed Ph+ acute leukemias

Original Article

Phase II study of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer

Erratum

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand

Original Article

Phase I clinical and pharmacokinetic study of oxaliplatin, irinotecan and capecitabine

Short Communication

Carbamazepine induces bioactivation of cyclophosphamide and thiotepa

Original Article

Efficacy of combination chemotherapy with capecitabine plus cisplatin in patients with unresectable hepatocellular carcinoma

Neu im Fachgebiet Onkologie

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

16.05.2024 alpha-1-Rezeptorantagonisten Nachrichten

Nach einer Prostatabiopsie treten häufig Probleme beim Wasserlassen auf. Ob sich das durch den periinterventionellen Einsatz von Alphablockern verhindern lässt, haben australische Mediziner im Zuge einer Metaanalyse untersucht.

Antikörper-Wirkstoff-Konjugat hält solide Tumoren in Schach

16.05.2024 Zielgerichtete Therapie Nachrichten

Trastuzumab deruxtecan scheint auch jenseits von Lungenkrebs gut gegen solide Tumoren mit HER2-Mutationen zu wirken. Dafür sprechen die Daten einer offenen Pan-Tumor-Studie.

Mammakarzinom: Senken Statine das krebsbedingte Sterberisiko?

15.05.2024 Mammakarzinom Nachrichten

Frauen mit lokalem oder metastasiertem Brustkrebs, die Statine einnehmen, haben eine niedrigere krebsspezifische Mortalität als Patientinnen, die dies nicht tun, legen neue Daten aus den USA nahe.

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

13.05.2024 Pankreaskarzinom Nachrichten

Gerade bei aggressiven Malignomen wie dem duktalen Adenokarzinom des Pankreas könnte Früherkennung die Therapiechancen verbessern. Noch jedoch klafft hier eine Lücke. Ein Studienteam hat einen Weg gesucht, sie zu schließen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise