STM Article Repository

Silibinin induces immunogenic cell death in cancer cells and enhances the induced immunogenicity by chemotherapy Sevda Jafari Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran http://orcid.org/0000-0002-7634-2619 Saba Heydarian Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Raymond Lai Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada Elnaz Mehdizadeh Aghdam Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Ommoleila Molavi Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran http://orcid.org/0000-0002-1820-7048

Introduction: Silibinin is a natural flavonoid compound known to induce apoptosis in cancer cells. Despite silibinin's safety and efficacy as an anticancer drug, its effects on inducing immunogenic cell death (ICD) are largely unknown. Herein, we have evaluated the stimulating effects of silibinin on ICD in cancer cells treated with silibinin alone or in combination with chemotherapy. Methods: The anticancer effect of silibinin, alone or in combination with doxorubicin or oxaliplatin (OXP), was assessed using the MTT assay. Compusyn software was used to analyze the combination therapy data. Western blotting was conducted to examine the level of STAT3 activity. Flow cytometry was used to analyze calreticulin (CRT) and apoptosis. The heat shock protein (HSP70), high mobility group box protein1 (HMGB1), and IL-12 levels were assessed by ELISA. Results: Compared to the negative control groups, silibinin induced ICD in CT26 and B16F10 cells and significantly enhanced the induction of this type of cell death by doxorubicin, and these changes were allied with substantial increases in the level of damage-associated molecular patterns (DAMPs) including CRT, HSP70, and HMGB1. Furthermore, conditioned media from cancer cells exposed to silibinin and doxorubicin was found to stimulate IL-12 secretion in dendritic cells (DCs), suggesting the link of this treatment with the induction of Th1 response. Silibinin did not augment the ICD response induced by OXP. Conclusion: Our findings showed that silibinin can induce ICD and it potentiates the induction of this type of cell death induced by chemotherapy in cancer cells.
04 27 2022 01 01 2023 51 61 1 10.34172/crossmark_policy bi.tbzmed.ac.ir false Tabriz University of Medical Sciences Tabriz University of Medical Sciences 2021-02-21 2021-05-31 2022-04-27 10.34172/bi.2022.23698 20230108213055 https://bi.tbzmed.ac.ir/Article/bi-23698 https://bi.tbzmed.ac.ir/PDF/bi-13-51.pdf https://bi.tbzmed.ac.ir/PDF/bi-13-51.pdf https://bi.tbzmed.ac.ir/PDF/bi-13-51.pdf https://bi.tbzmed.ac.ir/PDF/bi-13-51.pdf https://bi.tbzmed.ac.ir/PDF/bi-13-51.pdf 10.1158/0008-5472.CAN-09-3566 10.1007/s00018-020-03459-1 10.5301/tj.5000675 10.1007/978-3-319-67577-0_5 Pitt JM, Kroemer G, Zitvogel L. Immunogenic and non-immunogenic cell death in the tumor microenvironment. Tumor Immune Microenvironment in Cancer Progression and Cancer Therapy. Springer; 2017. p. 65-79. https://doi.org/10.1007/978-3-319-67577-0-5. 10.1038/cdd.2008.67 10.1016/j.bcp.2018.02.006 Radogna F, Diederich M. Stress-induced cellular responses in immunogenic cell death: Implications for cancer immunotherapy. Biochem Pharmacol 2018. 153: 12-23. https://doi.org/10.1016/j.bcp.2018.02.006. 10.1038/cmi.2013.59 10.1007/s10555-011-9273-4 10.3390/ijms19020594 10.4161/onci.25961 10.1007/s12272-019-01150-z Anticancer Res Cell death forms and HSP70 expression in U87 cells after ionizing radiation and/or chemotherapy Paolini A 31 3727 2011 10.1080/09205063.2020.1743946 10.34172/bi.2020.11 10.1016/j.ctrv.2017.06.003 10.1124/pr.58.3.10 10.1021/acs.molpharmaceut.6b01119 10.1007/s40199-020-00326-z 10.1016/j.ctrv.2015.04.008 10.1016/j.fct.2018.04.028 10.1016/j.tips.2015.10.001 10.1158/0008-5472.CAN-15-2770 10.1080/13880209.2016.1270972 10.3892/or.2017.5588 10.1038/sj.onc.1208627 10.1371/journal.pone.0173121 10.1146/annurev-immunol-032712-100008 10.4049/jimmunol.181.12.8576 10.1016/B978-0-12-812373-7.00010-3 Dheeraj A, Tailor D, Singh SP, Singh RP. Anticancer Attributes of Silibinin: Chemo-and Radiosensitization of Cancer. Role of Nutraceuticals in Cancer Chemosensitization: Elsevier; 2018. p. 199-220. https://doi.org/10.1016/B978-0-12-812373-7.00010-3. 10.1111/jcmm.14356 10.1111/j.1745-7254.2007.00691.x 10.3892/mmr.2018.9129 10.3892/ijo.2012.1568 Exp Dermatol Immune modulation by melanoma‐derived factors Ilkovitch D 17 977 2008 10.1111/j.1600-0625.2008.00779.x 10.3892/ijo.2012.1526 10.1158/1078-0432.CCR-04-1435 10.1158/0008-5472.CAN-11-0753 10.1007/s00262-009-0797-1 10.1158/0008-5472.CAN-15-1122 10.1038/onc.2009.356 10.3389/fimmu.2015.00187 10.3390/cancers3043856