Silymarin Mediates Apoptosis Through Activation of JNK/ERK Signaling Pathway in Human Colon Carcinoma Cells in Response to (60Co) Gamma Radiation
Mitu Lal1*, Saif Ahmad Khan1 and Damodar Gupta2
1Inter University Accelerator Centre (IUAC), Aruna Asafali Marg, New Delhi, India
2Institute of Nuclear Medicine and Allied Sciences (INMAS), Defence Research and Development Organization (DRDO), Brig. S.K Mazumdar Marg, Timarpur, Delhi, India
*Corresponding Author: Mitu Lal, Inter University Accelerator Centre (IUAC), Aruna Asafali Marg, New Delhi, India.
July 22, 2022; Published: September 18, 2022
Colon cancer is the third most common neoplasm worldwide and one of the major causes of death. Thus, major objective of present investigation was to identify and assess a natural molecule available in dietary sources which can sensitize colon carcinoma cells following radiation exposure. HCT-15 and RKO cells were pretreated (-30min) with silymarin followed by radiation (2 and 2.5Gy) exposure and samples were collected, analyzed at different time intervals (0-48 hrs in relation to radiation and silymarin + radiation time point respectively). Expression of proteins related to ERK/ JNK and mode of cell death was measured using western blotting (γ-H2AX, PCNA, ERK/JNK). A significant activation of JNK was observed in both the cells after treatment with silymarin and radiation. In all the samples effect was higher than silymarin alone and radiation with respect to combination group. An increase in apoptosis with increase in DNA damage was found to be accompanied with decreased SOD2 levels (0-48 hr) by combination treated group. In present investigation, silymarin was found to be potent inducer of cell death through ERK/JNK pathway. Silymarin was found to sensitize cells to radiation at non-toxic concentration and sub lethal radiation dose. Silymarin is already being utilized in traditional system of medicine (homeopathy, ayurveda and Chinese system of medicine) and therefore it possesses potential utility in future for treatment of colon cancer.
Keywords: Ionizing Radiation (IR); Silymarin; JNK; ERK; PCNA
- Mendez-Sanchez N., et al. “Superior silybin bioavailability of silybin-phosphatidylcholine complex in oily-medium soft-gel capsules versus conventional silymarin tablets in healthy volunteers”. BMC Pharmacology and Toxicology1 (2019): 5.
- Foster SA. Milk Thistle – Silybum marianum. American Botanical Council. No. 305, 1991. Milk thistle - CMS.Herbalgram.org Chinese Version - American Botanical Council 286-295.
- ElSayed AI., et al. “The Impact of Drought Stress on Antioxidant Responses and Accumulation of Flavonolignans in Milk Thistle (Silybum marianum (L.) Gaertn)”. Plants (Basel) 12 (2019).
- Liu CH., et al. “Antiviral Activities of Silymarin and Derivatives”. Molecules 8 (2019).
- Karimi G., et al. “"Silymarin", a promising pharmacological agent for treatment of diseases”. Iranian Journal of Basic Medical Sciences 4 (2011): 308-317.
- Sohrabi MJ., et al. “Silymarin-albumin nanoplex: Preparation and its potential application as an antioxidant in nervous system in vitro and in vivo”. International Journal of Pharmaceutics 572 (2019): 118824.
- Teksoy O., et al. “The Protective Effects of Silymarin on Thioacetamide-Induced Liver Damage: Measurement of miR-122, miR-192, and miR-194 Levels”. Applied Biochemistry and Biotechnology (2019).
- Jacobs BP., et al. “Milk thistle for the treatment of liver disease: a systematic review and meta-analysis”. American Journal of Medicine 6 (2002): 506-515.
- Di Nicolantonio F., et al. “Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer”. Journal of Clinical Oncology35 (2008): 5705-5712.
- Haller DG., et al. “Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089”. Journal of Clinical Oncology34 (2005): 8671-8678.
- Adam R., et al. “Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal”. Annals of Surgical Oncology4 (2001): 347-353.
- Duvall E and B Baumann. “An unusual accident during the administration of chemotherapy”. Cancer Nursing4 (1980): 305-306.
- Black LA and AC Presson. “Hazardous drugs”. Occupational Medicine 4 (1997): 669-685.
- Schreiber C., et al. “Uptake of antineoplastic agents in pharmacy personnel. Part II: study of work-related risk factors”. International Archives of Occupational and Environmental Health 1 (2003): 11-16.
- Lyons F. “IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans”. March (2012).
- Hazra B., et al. “The prospective role of plant products in radiotherapy of cancer: a current overview”. Frontiers in Pharmacology 2 (2011): 94.
- Urick ME., et al. “Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition”. Clinical Cancer Research15 (2011): 5038-5047.
- Banath JP and PL Olive. “Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks”. Cancer Research15 (2003): 4347-4350.
- Mitu Lal DG. “Studies on radiation sensitization efficacy by silymarin in colon carcinoma cells”. Discoveries (2016).
- Gupta D., et al. “Radiation protection of HepG2 cells by Podophyllum hexandrum Royale”. Molecular and Cellular Biochemistry1-2 (2003): 27-40.
- Gao YJ and RR Ji. “Activation of JNK pathway in persistent pain”. Neuroscience Letter3 (2008): 180-183.
- Wang X., et al. “Requirement for ERK activation in cisplatin-induced apoptosis”. Journal of Biological Chemistry 50 (2000): 39435-39443.
- Fang J., et al. “Therapeutic strategies by modulating oxygen stress in cancer and inflammation”. Advanced Drug Delivery Reviews4 (2009): 290-302.
- Fang J., et al. “Tumor-targeted induction of oxystress for cancer therapy”. Journal of Drug Target7-8 (2007): 475-486.
- Xu W., et al. “The role of nitric oxide in cancer”. Cell Research5-6 (2002): 311-320.
- Caulfield JL., et al. “Nitric oxide-induced interstrand cross-links in DNA”. Chemical Research in Toxicology 5 (2003): 571-574.
- Shen HM and ZG Liu. “JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species”. Free Radical Biology and Medicine6 (2006): 928-939.
- Lu LY., et al. “Antioxidant induces DNA damage, cell death and mutagenicity in human lung and skin normal cells”. Scientific Report 3 (2013): 3169.
- Adhikari M., et al. “Evaluation of silymarin as a promising radioprotector”. Z Naturforsch C5-6 (2010): 337-46.
- Munshi A and R Ramesh. “Mitogen-activated protein kinases and their role in radiation response”. Genes Cancer9-10 (2010): 401-408.