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Article

Valproic acid overcomes hypoxia-induced resistance to apoptosis

  • Authors:
    • Šimon Cipro
    • Jana Hřebačková
    • Jan Hraběta
    • Jitka Poljaková
    • Tomáš Eckschlager
  • View Affiliations / Copyright

    Affiliations: Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, V Úvalu 84, 150 00 Prague 5, Czech Republic, 2nd Medical School, Charles University, V Úvalu 84, 150 00 Prague 5, Czech Republic
  • Pages: 1219-1226
    |
    Published online on: December 6, 2011
       https://doi.org/10.3892/or.2011.1577
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Abstract

Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O2) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O2), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment.
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1 

Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Furchert SE, Lanvers-Kaminsky C, Juurgens H, Jung M, Loidl A and Frühwald MC: Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer. 120:1787–1794. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Mossman D and Scott RJ: Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation. PloS One. 6:e231272011. View Article : Google Scholar : PubMed/NCBI

4 

Santini V, Gozzini A and Ferrari G: Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr Drug Metab. 8:383–393. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Bokelmann I and Mahlknecht U: Valproic acid sensitizes chronic lymphocytic leukemia cells to apoptosis and restores the balance between pro- and antiapoptotic proteins. Mol Med. 14:20–27. 2007.PubMed/NCBI

6 

Fullgrabe J, Hajji N and Joseph B: Cracking the death code: apoptosis-related histone modifications. Cell Death Differ. 1:1238–1243. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Hrebackova J, Poljakova J, Eckschlager T, et al: Histone deacetylase inhibitors valproate and trichostatin A are toxic to neuroblastoma cells and modulate cytochrome P450 1A1, 1B1 and 3A4 expression in these cells. Interdiscip Toxicol. 2:205–210. 2009. View Article : Google Scholar

8 

Cinatl J, Scholz M, Driever PH, et al: Antitumor activity of sodium valproate in cultures of human neuroblastoma cells. Anticancer Drugs. 7:766–773. 1996. View Article : Google Scholar : PubMed/NCBI

9 

Michaelis M, Suhan T and Cinatl J, Driever PH and Cinatl J: Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo. Int J Oncol. 25:1795–1799. 2004.

10 

Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Vaupel P, Kallinowski F and Okunieff P: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49:6449–6465. 1989.PubMed/NCBI

12 

Hussein D, Estlin EJ, Dive C and Makin GW: Chronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells. Mol Cancer Ther. 5:2241–2250. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Lara PC, Lloret M, Clavo B, et al: Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression. Radiat Oncol. 4:292009. View Article : Google Scholar : PubMed/NCBI

14 

Song X, Liu X, Chi W, et al: Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol. 58:776–784. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Giuntoli S, Rovida E, Barbetti V, Cipolleschi MG, Olivotto M and Dello Sbarba P: Hypoxia suppresses BCR/Abl and selects imatinib-insensitive progenitors within clonal CML populations. Leukemia. 20:1291–1293. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Huang LE, Bindra RS, Glazer PM and Harris AL: Hypoxia-induced genetic instability - a calculated mechanism underlying tumor progression. J Mol Med (Berl). 85:139–148. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Brizel DM, Scully SP, Harrelson JM, et al: Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56:941–943. 1996.PubMed/NCBI

18 

Hockel M, Schlenger K, Aral B, et al: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56:4509–4515. 1996.PubMed/NCBI

19 

Hockel M, Schlenger K, Hockel S and Vaupel P: Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 59:4525–4528. 1999.PubMed/NCBI

20 

Bossy-Wetzel E and Green DR: Detection of apoptosis by annexin V labeling. Methods Enzymol. 322:15–18. 2000. View Article : Google Scholar : PubMed/NCBI

21 

Pfaffl MW, Horgan GW and Dempfle L: Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30:e362002. View Article : Google Scholar : PubMed/NCBI

22 

Yin X-M: Bid, a BH3-only multi-functional molecule, is at the cross road of life and death. Gene. 369:7–19. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Baek JH, Jang JE, Kang CM, Chung HY, Kim ND and Kim KW: Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene. 19:4621–4631. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Liu X-H, Yu EZ, Li Y-Y and Kagan E: HIF-1alpha has an anti-apoptotic effect in human airway epithelium that is mediated via Mcl-1 gene expression. J Cell Biochem. 97:755–765. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Lee J-W, Bae S-H, Jeong J-W, Kim S-H and Kim K-W: Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 36:1–12. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Semenza GL: HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 88:1474–1480. 2000.PubMed/NCBI

27 

Shannon AM, Bouchier-Hayes DJ, Condron CM and Toomey D: Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 29:297–307. 2003. View Article : Google Scholar : PubMed/NCBI

28 

Um JH, Kang CHD, Bae JH, et al: Association of DNA-dependent protein kinase with hypoxia inducible factor-1 and its implication in resistance to anticancer drugs in hypoxic tumor cells. Exp Mol Med. 36:233–242. 2004. View Article : Google Scholar : PubMed/NCBI

29 

Graeber TG, Osmanian C, Jacks T, et al: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 379:88–91. 1996. View Article : Google Scholar : PubMed/NCBI

30 

Liu L, Ning X, Sun L, et al: Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 99:121–128. 2008.PubMed/NCBI

31 

Piret J-P, Mottet D, Raes M and Michielis C: Is HIF-1alpha a pro- or an anti-apoptotic protein? Biochem Pharmacol. 64:889–892. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Suzuki H, Tomida a and Tsuruo T: Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene. 20:5779–5788. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Kim SH, Jeong JW, Park JA, et al: Regulation of the HIF-1α stability by histone deacetylases. Oncol Rep. 17:647–651. 2007.

34 

An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV and Neckers LM: Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature. 392:405–408. 1998. View Article : Google Scholar : PubMed/NCBI

35 

Sendoel A, Kohler I, Fellmann C, Lowe WS and Hengartner OM: HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature. 465:577–585. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Nardinocchi L, Puca R and Orazi GD: HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging. 3:33–43. 2011.

37 

Flamant L, Notte A, Ninane N, Raes M and Michiels C: Anti-apoptotic role of HIF-1 and AP-1 in paclitaxel exposed breast cancer cells under hypoxia. Mol Cancer. 9:1912010. View Article : Google Scholar : PubMed/NCBI

38 

Dong Z, Venkatachalam Ma, Wang J, et al: Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia. Hif-1-independent mechanisms. J Biol Chem. 276:18702–18709. 2001. View Article : Google Scholar : PubMed/NCBI

39 

Piret J-P, Cosse J-P, Ninane N, Raes M and Michiels C: Hypoxia protects HepG2 cells against etoposide-induced apoptosis via a HIF-1-independent pathway. Exp Cell Res. 312:2908–2920. 2006. View Article : Google Scholar : PubMed/NCBI

40 

Chen G, Yuan PX, Jiang YM, Huang LD and Manji HK: Valproate robustly enhances AP-1 mediated gene expression. Brain Res Mol Brain Res. 64:52–58. 1999. View Article : Google Scholar : PubMed/NCBI

41 

Hrebackova J, Hrabeta J and Eckschlager T: Valproic acid in the complex therapy of malignant tumors. Curr Drug Targets. 11:361–379. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Catalano MG, Fortunati N, Pugliese M, et al: Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab. 90:1383–1389. 2005. View Article : Google Scholar : PubMed/NCBI

43 

Nebbioso A, Clarke N, Voltz E, et al: Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med. 11:77–84. 2005. View Article : Google Scholar : PubMed/NCBI

44 

Muhlethaler-Mottet A, Meier R, Flahaut M, et al: Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells. Mol Cancer. 7:552008. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Cipro Š, Hřebačková J, Hraběta J, Poljaková J and Eckschlager T: Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncol Rep 27: 1219-1226, 2012.
APA
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., & Eckschlager, T. (2012). Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncology Reports, 27, 1219-1226. https://doi.org/10.3892/or.2011.1577
MLA
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., Eckschlager, T."Valproic acid overcomes hypoxia-induced resistance to apoptosis". Oncology Reports 27.4 (2012): 1219-1226.
Chicago
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., Eckschlager, T."Valproic acid overcomes hypoxia-induced resistance to apoptosis". Oncology Reports 27, no. 4 (2012): 1219-1226. https://doi.org/10.3892/or.2011.1577
Copy and paste a formatted citation
x
Spandidos Publications style
Cipro Š, Hřebačková J, Hraběta J, Poljaková J and Eckschlager T: Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncol Rep 27: 1219-1226, 2012.
APA
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., & Eckschlager, T. (2012). Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncology Reports, 27, 1219-1226. https://doi.org/10.3892/or.2011.1577
MLA
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., Eckschlager, T."Valproic acid overcomes hypoxia-induced resistance to apoptosis". Oncology Reports 27.4 (2012): 1219-1226.
Chicago
Cipro, Š., Hřebačková, J., Hraběta, J., Poljaková, J., Eckschlager, T."Valproic acid overcomes hypoxia-induced resistance to apoptosis". Oncology Reports 27, no. 4 (2012): 1219-1226. https://doi.org/10.3892/or.2011.1577
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