• Maha S. Al-keilani Jordan University of Science and Technology, College of Pharmacy, Department of Clinical Pharmacy, P.O. Box 3030, Irbid 22110, Jordan
  • Dua H. Alsmadi Jordan University of Science and Technology, College of Pharmacy, Department of Clinical Pharmacy, P.O. Box 3030, Irbid 22110, Jordan


Objective: The main objective of this study was to evaluate the ability of sodium phenylbutyrate (NaPB) to enhance the cytotoxicity of 5-fluorouracil, oxaliplatin, and irinotecan against colorectal cancer cell lines expressing wild-type and mutant p53.

Methods: The antiproliferative effect of NaPB alone or in combination with 5-fluorouracil, oxaliplatin, or irinotecan in HCT-116 and HT-29 colorectal cancer cell lines was investigated using the MTT cell proliferation assay. IC50 values were calculated using Compusyn Software 1.0 (Combosyn Inc.). Synergy values (R) were calculated using the ratio of IC50 of each primary drug alone divided by combination IC50s. For each two pairs of experiments, student’s t-test was used for analysis. In combination studies, one-way ANOVA test; Tukey post-hoc testing was performed using R 3.3.2 software. P-value<0.05 was considered significant.

Results: NaPB inhibited the growth of HCT-116 and HT-29 cell lines in a dose-dependent manner (IC50s 4.7 mmol, and 10.1 mmol, respectively). HT-29 cell lines (mutant p53) were more sensitive to NaPB at low concentrations (<4 mmol). Moreover, the addition of NaPB to HCT-116 and HT-29 with 5-fluorouracil, oxaliplatin, or irinotecan synergistically induced the antiproliferative effect (R>1.6, p-value<0.05).

Conclusion: NaPB enhanced the cytotoxicity of conventional chemotherapy against colorectal cancer cell lines harboring wild-type or mutant p53. Thus NaPB is a promising potential adjuvant chemotherapy in colorectal cancer.

Keywords: Colorectal cancer, Histone deacetylase inhibitor, Sodium phenylbutyrate, Adjuvant chemotherapy


Download data is not yet available.


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.
2. Abdel-Razeq H, Attiga F, Mansour A. Cancer care in Jordan. Hematol Oncol Stem Cell Ther 2015;8:64-70.
3. Midgley R, Kerr D. Colorectal cancer. Lancet 1999;353:391-9.
4. Benson AB. 3rd. Adjuvant chemotherapy of stage III colon cancer. Semin Oncol 2005;32(6 Suppl 9):S74-7.
5. Kanwar SS, Poolla A, Majumdar AP. Regulation of colon cancer recurrence and development of therapeutic strategies. World J Gastrointest Pathophysiol 2012;3:1-9.
6. De Mestier L, Manceau G, Neuzillet C, Bachet JB, Spano JP, Kianmanesh R, et al. Primary tumor resection in colorectal cancer with unresectable synchronous metastases: a review. World J Gastrointest Oncol 2014;6:156-69.
7. Boyer J, McLean EG, Aroori S, Wilson P, McCulla A, Carey PD, et al. Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. Clin Cancer Res 2004;10:2158-67.
8. Carethers JM. Systemic treatment of advanced colorectal cancer: tailoring therapy to the tumor. Ther Adv Gastroenterol 2008;1:33-42.
9. Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 2016;8:57-84.
10. Ade Arsianti, Fadilah Fadilah, Kusmardi Kusmardi, Hiroki Tanimoto, Kiyomi Kakiuchi. Design and molecular docking study of antimycin A 3 analogues as inhibitors of anti-apoptotic Bcl-2 of breast cancer design and molecular docking study of antimycin A 3 analogues as inhibitors of anti-apoptotic Bcl-2 of breast cancer. Asian J Pharm Clin Res 2015;8:120-4.
11. Mottamal M, Zheng S, Huang TL, Wang G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 2015;20:3898-941.
12. Ansari J, Shackelford RE, El-Osta H. Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res 2016;5:155-71.
13. Bolden JE, Shi W, Jankowski K, Kan CY, Cluse L, Martin BP, et al. HDAC inhibitors induce tumour-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis 2013;4:e519.
14. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27-36.
15. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014;6:1769-92.
16. Hu E, Dul E, Sung CM, Chen Z, Kirkpatrick R, Zhang GF, et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 2003;307:720-8.
17. Monneret C. Histone deacetylase inhibitors. Eur J Med Chem 2005;40:1-13.
18. Iannitti T, Palmieri B. Clinical and experimental applications of sodium phenylbutyrate. Drugs R D 2011;11:227-49.
19. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discovery 2006;5:769-84.
20. Tailor D, Hahm ER, Kale RK, Singh SV, Singh RP. Sodium butyrate induces DRP1-mediated mitochondrial fusion and apoptosis in human colorectal cancer cells. Mitochondrion 2014;16:55-64.
21. Jessi Shaji, Ipshita Menon. Recent advances in nanocarrier based therapeutic and diagnostic tools for colorectal cancer. Int J Curr Pharm Res 2015;7:9-16.
22. Richard SM, Martinez Marignac VL. Sensitization to oxaliplatin in HCT116 and HT29 cell lines by metformin and ribavirin and differences in response to mitochondrial glutaminase inhibition. J Cancer Res Ther 2015;11:336-40.
23. Ngugi M Piero, Njagi M Joan. Cancer: a molecular curse? Int J Curr Pharm Res 2015;7:1-3.
24. Caulin AF, Maley CC. Peto's paradox: evolution's prescription for cancer prevention. Trends Ecol Evol 2011;26:175-82.
25. Na YS, Kim SM, Jung KA, Yang SJ, Hong YS, Ryu MH, et al. Effects of the HDAC inhibitor CG2 in combination with irinotecan, 5-fluorouracil, or oxaliplatin on HCT116 colon cancer cells and xenografts. Oncol Rep 2010;24:1509-14.
26. Tumber A, Collins LS, Petersen KD, Thougaard A, Christiansen SJ, Dejligbjerg M, et al. The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol 2007;60:275-83.
27. Na YS, Jung KA, Kim SM, Hong YS, Ryu MH, Jang SJ, et al. The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models. Cancer Chemother Pharmacol 2011;68:389-98.
28. Flis S, Gnyszka A, Splawinski J. HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. Biochem Biophys Res Commun 2009;387:336-41.
29. Candeias MM, Hagiwara M, Matsuda M. Cancer-specific mutations in p53 induce the translation of Delta160p53 promoting tumorigenesis. EMBO Rep 2016;17:1542-51.
30. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 2002;416:560-4.
31. Kenzelmann Broz D, Spano Mello S, Bieging KT, Jiang D, Dusek RL, Brady CA, et al. Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev 2013;27:1016-31.
32. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2:a001008.
33. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013;502:333-9.
34. Magrini R, Bhonde MR, Hanski ML, Notter M, Scherubl H, Boland CR, et al. Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 2002;101:23-31.
35. Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 1999;59:1391-9.
36. Wang Z, Sun Y. Targeting p53 for novel anticancer therapy. Transl Oncol 2010;3:1-12.
37. Sri Hartati Yuliani, Clara Dewi Anggraeni, Winda Sekarjati, Andung Panjalu, Enade Perdana Istyastono, Agustina Setiawati. Cytotoxic activity of anredera cordifolia leaf extract on hela cervical cancer cells through the p53-independent pathway. Asian J Pharm Clin Res 2015;8:328-31.
303 Views | 729 Downloads
How to Cite
Al-keilani, M. S., and D. H. Alsmadi. “THE HDAC INHIBITOR SODIUM PHENYLBUTYRATE ENHANCES THE CYTOTOXICITY INDUCED BY 5-FLUOROURACIL, OXALIPLATIN, AND IRINOTECAN IN COLORECTAL CANCER CELL LINES”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 10, no. 1, Jan. 2018, pp. 155-9, doi:10.22159/ijpps.2018v10i1.22947.
Original Article(s)