Valproic acid enhances the paclitaxel activity in respiratory tract cancer cells

Authors

  • Ahmed Salim Kadhim Al-Khafaji Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine University of Liverpool, Liverpool, UK
  • Ghaliah Alnefaie Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine University of Liverpool, Liverpool, UK
  • Ahmed Majeed Al-Shammari Experimental Therapy Department, Iraqi Center for Cancer and Medical, Genetic Research, Mustansiriyah University, Baghdad, Iraq

DOI:

https://doi.org/10.22317/jcms.v5i4.658

Keywords:

Valproic acid, paclitaxel, lung cancer, Head and Neck cancer, Epigenetic

Abstract

Objective: Epigenetic therapies have already been introduced into clinical cancer management.  The main objective of this study is to explore the potential of modulating paclitaxel efficiency using two epigenetic modifiers; valproic acid and decitabin.

Methods: the potential sensitisation of lung and oral cancer cells to paclitaxel was examined by two well-known epigenetic modifiers; the DNA methyltransferase (DNMT) inhibitor Decidabine and histone deacetylase (HDAC) class I inhibitor Valproic acid (VPA). The effect epigenetic modifiers were tested using qPCR and pyrosequencing techniques utilising respiratory tract cancerous tissues and cell lines.

Results: The results exhibited that VPA was an effective epigenetic sensitizer for treating lung and head and neck cancerous cells (A549, SKLU1 and BHY). 48 hours prior to paclitaxel addition, a significant increase (p<0.01) of the paclitaxel toxicity was observed when the cancer cells pre-treated with VPA for 48hr and subsequently with paxlitaxel for 72 hours.  Interestingly, mRNA expression of AURKA was reduced by VPA treatment. The result also demonstrated that p53 status was involved in VPA- mediated paclitaxel sensitisation of HBEC cell lines to paclitaxel. VPA seems to potentiate p53 wild type cells (HBEC-3KT) to paclitaxel, while p53 HBEC knockouts showed less cytotoxic effect of paclitaxel after exposure to 0.5 mM VPA. On the other hand, decitabin was not efficient to sensitise any of the cell lines to paclitaxel when used in either a synchronous or a preceding manner. In addition, the pyrosequencing analysis of the methylation status of the different gene promoters in the lung tumour and normal tissues showed that all the promoters were unmethylated.

Conclusion: It can be concluded that the epigenetic modifier VPA can alter the response of cancer cells to paclitaxel treatment. Further investigation is needed to explore the epigenetic mechanism of sensitising cancerous cells to paclitaxel.

References

1. Braiteh F, Soriano AO, Garcia-Manero G, et al. Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. Oct 1 2008;14(19):6296-6301.
2. Chu BF, Karpenko MJ, Liu Z, et al. Phase I study of 5-aza-2'-deoxycytidine in combination with valproic acid in non-small-cell lung cancer. Cancer chemotherapy and pharmacology. Jan 2013;71(1):115-121.
3. Roy Choudhury S, Karmakar S, Banik NL, Ray SK. Valproic acid induced differentiation and potentiated efficacy of taxol and nanotaxol for controlling growth of human glioblastoma LN18 and T98G cells. Neurochemical research. Dec 2011;36(12):2292-2305.
4. Catalano MG, Poli R, Pugliese M, Fortunati N, Boccuzzi G. Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines. Endocrine-related cancer. Sep 2007;14(3):839-845.
5. Tesei A, Brigliadori G, Carloni S, et al. Organosulfur derivatives of the HDAC inhibitor valproic acid sensitize human lung cancer cell lines to apoptosis and to cisplatin cytotoxicity. Journal of cellular physiology. Oct 2012;227(10):3389-3396.
6. Erlich RB, Rickwood D, Coman WB, Saunders NA, Guminski A. Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas. Cancer chemotherapy and pharmacology. Feb 2009;63(3):381-389.
7. Bailey VJ, Easwaran H, Zhang Y, et al. MS-qFRET: a quantum dot-based method for analysis of DNA methylation. Genome research. Aug 2009;19(8):1455-1461.
8. Kim CH. Druggable targets of squamous cell lung cancer. Tuberculosis and respiratory diseases. Dec 2013;75(6):231-235.
9. Timofeeva MN, Hung RJ, Rafnar T, et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Human molecular genetics. Nov 15 2012;21(22):4980-4995.
10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 20 2005;23(24):5542-5551.
11. Zighetti ML, Fontana G, Lussana F, et al. Effects of chronic administration of valproic acid to epileptic patients on coagulation tests and primary hemostasis. Epilepsia. May 2015;56(5):e49-52.
12. Tremolizzo L, Difrancesco JC, Rodriguez-Menendez V, et al. Valproate induces epigenetic modifications in lymphomonocytes from epileptic patients. Progress in neuro-psychopharmacology & biological psychiatry. Oct 1 2012;39(1):47-51.
13. Chen J, Liu J. Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint. Nature communications. 2014;5:4795.
14. King TC, Akerley W, Fan AC, et al. p53 mutations do not predict response to paclitaxel in metastatic nonsmall cell lung carcinoma. Cancer. Aug 15 2000;89(4):769-773.
15. Vogt U, Zaczek A, Klinke F, Granetzny A, Bielawski K, Falkiewicz B. p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer. Journal of cancer research and clinical oncology. Mar 2002;128(3):141-147.
16. Das GC, Holiday D, Gallardo R, Haas C. Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition. Cancer letters. Apr 26 2001;165(2):147-153.
17. Duarte ML, de Moraes E, Pontes E, et al. Role of p53 in the induction of cyclooxygenase-2 by cisplatin or paclitaxel in non-small cell lung cancer cell lines. Cancer letters. Jun 28 2009;279(1):57-64.
18. Zhang XH, Rao M, Loprieato JA, et al. Aurora A, Aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer biology & therapy. Sep 2008;7(9):1388-1397.
19. Al-Khafaji ASK, Marcus MW, Davies MPA, et al. AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer. Oncol Lett. Jun 2017;13(6):4463-4468.

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Published

2019-08-26

How to Cite

Al-Khafaji, A. S. K., Alnefaie, G., & Al-Shammari, A. M. (2019). Valproic acid enhances the paclitaxel activity in respiratory tract cancer cells. Journal of Contemporary Medical Sciences, 5(4), 208–213. https://doi.org/10.22317/jcms.v5i4.658