Thai Ho

Introduction: Colorectal cancer (CRC) is the 3^rd leading cancer in the United States with a mortality rate of 14.8 per year. Although the incidence of CRC has decreased over the past 2 decades in the U.S. the incidence of CRC has increased drastically in the eastern hemisphere. Many studies have attributed the increased incidence rate to poor dietary habits (CRC).¹ Consuming high fat, processed foods lead to increased oxidative stress on the body which increases the likelihood of epigenetic modifications that contribute to CRC development.² However, studies have found that consumption of foods with high concentrations of isothiocyanates reduces the risk of development CRC through epigenetic mechanisms. These studies show that certain ITC’s decreased activity of DNMT1a, PRMT5/MEP50, and HDAC’s and subsequently decreased cell viability.^3-5 These findings suggest a potential chemotherapeutic treatment for CRC and other cancers. Methods: LNCaP cells were treated with differing concentrations of isothiocyanates. qPCR was performed to obtained genetic material for analysis. Southern, Northern, and Western blots were performed to determine the expression of DMNT’s, HDAC’s, and RASSF1A. Colony formation and assays were conducted to determine the viability of the treated cell line. The same method was performed on human squamous cell carcinoma cell line SCC-13, epidermoid carcinoma cell line A431 and HaCaT cells to evaluate the function of PRMT5/MEP50. Results: LNCaP cells treated with PEITC showed significantly enhanced RASSF1A expression through decreased DMNT1/3a activity in a dose dependent manner. Treatment of LNCaP also enhanced apoptosis through activation of the caspases 3/7. ⁴ Studies show that SFN did not result in any substantive change in MEP50 or PRMT5 mRNA but nonetheless resulted in decreased tumor formation.³ Treatment with ITC’s was associated with decrease tumor cell proliferation and decreased gene methylation activity.⁵ Conclusions: Studies have found that PEITC and SFN have cancer chemopreventive effects. PETIC and SFN exert their effects through dampening and in some cases reversing the epigenetic silencing activity of DNMT1a, PRMT5/MEP50, and HDAC’s in a dose dependent manner. These studies suggest that ITC’s are a potential treatment method for CRC and calls for clinical trials to further examine the efficacy of ITC administration for treatment of CRC in vivo.

1. Marley, A. R., & Nan, H. (2016). Epidemiology of colorectal cancer. International Journal of Molecular Epidemiology and Genetics, 7(3), 105–114.
2. Lee, J. H., Khor, T. O., Shu, L., Su, Z.-Y., Fuentes, F., & Kong, A.-N. T. (2013). Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacology & Therapeutics, 137(2), 153–171. https://doi.org/10.1016/j.pharmthera.2012.09.008
3. Saha, K., Fisher, M. L., Adhikary, G., Grun, D., & Eckert, R. L. (2017). Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation. Carcinogenesis, 38(8), 827–836. https://doi.org/10.1093/carcin/bgx044
4. Boyanapalli, S. S. S., Li, W., Fuentes, F., Guo, Y., Ramirez, C. N., Gonzalez, X.-P., … Kong, A.-N. T. (2016). Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells. Pharmacological Research, 114, 175–184. https://doi.org/10.1016/j.phrs.2016.10.021
5. Zhang, C., Su, Z.-Y., Khor, T. O., Shu, L., & Kong, A.-N. T. (2013). Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation. Biochemical Pharmacology, 85(9), 1398–1404. https://doi.org/10.1016/j.bcp.2013.02.010
6. Royston, K., Udayakumar, N., Lewis, K., & Tollefsbol, T. (2017). A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells. International Journal of Molecular Sciences, 18(5), 1092. https://doi.org/10.3390/ijms18051092