Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

Domínguez-Gómez,G.; Díaz-Chávez,J.; Chávez-Blanco,A.; Gonzalez-Fierro,A.; Jiménez-Salazar,J. E.; Damián-Matsumura,P.; Gómez-Quiroz,L. E.; Dueñas-González,A.

doi:10.3892/or.2014.3661

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

Authors:
- G. Domínguez-Gómez
- J. Díaz-Chávez
- A. Chávez-Blanco
- A. Gonzalez-Fierro
- J. E. Jiménez-Salazar
- P. Damián-Matsumura
- L. E. Gómez-Quiroz
- A. Dueñas-González
View Affiliations

Affiliations: Postgraduate Program on Experimental Biology, Autonomous Metropolitan University at Iztapalapa, Mexico, Unit of Biomedical Research in Cancer, Biomedical Research Institute, National Autonomous University of Mexico/National Cancer Institute, Mexico, Department of Reproductive Biology, Autonomous Metropolitan University at Iztapalapa, Mexico, Department of Health Sciences, Autonomous Metropolitan University at Iztapalapa, Mexico
Published online on: December 9, 2014 https://doi.org/10.3892/or.2014.3661
Pages: 721-728

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effect of DNA alkylating agents on BRCA1‑ and BRCA2-deficient cell lines. The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide (NAM) on breast cancer cells with different BRCA1 expression or function, such as BRCA1‑deficient MDA-MB-436 cells, low expression BRCA1 MCF-7 cells, and the BRCA1 wild‑type MDA-MB-231 cells, to demonstrate its effects as a chemo‑ or radiosensitizing agent. PARP activity was analyzed in MDA-MB-436, MCF-7 and MDA-MB-231 breast cancer cells subjected or not to NAM. Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence. Crystal violet assays were used to test growth inhibition and the chemo‑ and radiosensitization effects of NAM were investigated using clonogenic assays. Significant differences among data sets were determined using two-tailed ANOVA and Bonferroni tests. We demonstrated that NAM reduces PARP activity in vitro, and in cells subjected or not to DNA damage, it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA-MB-436 and MCF-7 cells. Downregulation of PARP1 with siRNA led to modest growth inhibition, which was further increased by cisplatin. Nicotinamide also induced radiosensitization in MDA-MB-436 and MDA-MB-231 cells. In conclusion, NAM may be used as a chemo‑ or radiosensitizing agent regardless of the BRCA1 status in breast cancer.

View Figures

View References

1	Davar D, Beumer JH, Hamieh L and Tawbi H: Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 19:3907–3921. 2012. View Article : Google Scholar : PubMed/NCBI
2	Hirai T, Shirai H, Fujimori H, Okayasu R, Sasai K and Masutani M: Radiosensitization effect of poly(ADP-ribose) polymerase inhibition in cells exposed to low and high liner energy transfer radiation. Cancer Sci. 103:1045–1050. 2012. View Article : Google Scholar : PubMed/NCBI
3	Michels J, Vitale I, Senovilla L, et al: Synergistic interaction between cisplatin and PARP inhibitors in non-small cell lung cancer. Cell Cycle. 12:877–883. 2013. View Article : Google Scholar : PubMed/NCBI
4	De Soto JA, Wang X, Tominaga Y, et al: The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors. Int J Biol Sci. 2:179–185. 2006. View Article : Google Scholar : PubMed/NCBI
5	Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434:913–917. 2005. View Article : Google Scholar : PubMed/NCBI
6	Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 434:917–921. 2005. View Article : Google Scholar : PubMed/NCBI
7	Murphy CG and Moynahan ME: BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J. 16:39–47. 2010. View Article : Google Scholar : PubMed/NCBI
8	Hilton JF, Hadfield MJ, Tran MT and Shapiro GI: Poly(ADP-ribose) polymerase inhibitors as cancer therapy. Front Biosci. 1:1392–1406. 2013. View Article : Google Scholar
9	Gupta SC, Sung B, Prasad S, Webb LJ and Aggarwal BB: Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci. 34:508–157. 2013. View Article : Google Scholar : PubMed/NCBI
10	Dueñas-González A, García-López P, Herrera LA, Medina-Franco JL, González-Fierro A and Candelaria M: The prince and the pauper. A tale of anticancer targeted agents. Mol Cancer. 7:822008. View Article : Google Scholar : PubMed/NCBI
11	Surjana D, Halliday GM and Damian DL: Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. J Nucleic Acids. 2010:pii: 157591. 2010. View Article : Google Scholar : PubMed/NCBI
12	Knip M, Douek IF, Moore WP, et al: European Nicotinamide Diabetes Intervention Trial Group Safety of high-dose nicotinamide: a review. Diabetologia. 43:1337–1345. 2000. View Article : Google Scholar : PubMed/NCBI
13	Virag L and Szabo C: The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 54:375–342. 2002. View Article : Google Scholar : PubMed/NCBI
14	Chen G and Zeller WJ: Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo. Cancer Chemother Pharmacol. 3:157–162. 1993. View Article : Google Scholar
15	Kaanders JH, Bussink J and Van der Kogel AJ: ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol. 3:728–737. 2002. View Article : Google Scholar : PubMed/NCBI
16	Janssens GO, Rademakers SE, Terhaard CH, et al: Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol. 30:1777–1783. 2012. View Article : Google Scholar : PubMed/NCBI
17	Bernier J, Denekamp J, Rojas A, et al: ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative group of radiotherapy of the european organization for research and treatment of cancer (EORTC). Radiother Oncol. 55:111–119. 2000. View Article : Google Scholar : PubMed/NCBI
18	Bernier J, Denekamp J, Rojas A, et al: ARCON: accelerated radiotherapy with carbogen and nicotinamide in non-small cell lung cancer: a phase I/II study by the EORTC. Radiother Oncol. 52:149–56. 1999. View Article : Google Scholar : PubMed/NCBI
19	Handfield-Jones S, Jones SK and Peachey RD: Nicotinamide treatment in diabetes. Br J Dermatol. 116:2771987. View Article : Google Scholar : PubMed/NCBI
20	Niren NM: Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis. 77(1 Suppl): 11–16. 2006.PubMed/NCBI
21	Kolb H and Burkart V: Nicotinamide in type 1 diabetes. Mechanism of action revisited. Diabetes Care. 22(Suppl 2): B16–B20. 1999.PubMed/NCBI
22	Vallely JF, Lovegrove TD and Hobbs GE: Nicotinic acid and nicotinamide in the treatment of chronic schizophrenia. Can Psychiatr Assoc J. 16:433–435. 1971.PubMed/NCBI
23	Jung-Hynes B, Nihal M, Zhong W and Ahmad N: Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem. 284:3823–3832. 2009. View Article : Google Scholar :
24	Audrito V, Vaisitti T, Rossi D, et al: Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res. 71:4473–4483. 2011. View Article : Google Scholar : PubMed/NCBI
25	Evers B, Drost R, Schut E, et al: Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res. 14:3916–3925. 2008. View Article : Google Scholar : PubMed/NCBI
26	Löser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA and Chalmers AJ: Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol Cancer Ther. 9:1775–1787. 2010. View Article : Google Scholar : PubMed/NCBI
27	Wang T, Cui H, Ma N and Jiang Y: Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis. Oncol Lett. 6:600–604. 2013.PubMed/NCBI
28	Gong DJ, Zhang JM, Yu M, Zhuang B and Guo QQ: Inhibition of SIRT1 combined with gemcitabine therapy for pancreatic carcinoma. Clin Interv Aging. 8:889–897. 2013.PubMed/NCBI
29	Dragovic J, Kim SH, Brown SL and Kim JH: Nicotinamide pharmacokinetics in patients. Radiother Oncol. 36:225–228. 1995. View Article : Google Scholar : PubMed/NCBI
30	Bernier J, Stratford MR, Denekamp J, et al: Pharmacokinetics of nicotinamide in cancer patients treated with accelerated radiotherapy: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer. Radiother Oncol. 48:123–133. 1998. View Article : Google Scholar : PubMed/NCBI
31	Horsman MR, Hoyer M, Honess DJ, Dennis IF and Overgaard J: Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy. Radiother Oncol. 27:131–139. 1993. View Article : Google Scholar : PubMed/NCBI