Issue
Lowered Cyclin E levels increase the efficiency and the specificity of capsaicin against cancerous cells of mesothelium
Corresponding Author(s) : Sabahattin Cömertpay
Cellular and Molecular Biology,
Vol. 66 No. 6: Issue 6
Abstract
Capsaicin is one of the most extensively studied phytochemicals and its cytotoxicity on various types of cancer has been demonstrated both in vitro and in vivo. The evaluation of its effect on mesothelioma, however, has remained quite limited. In this study, we investigated the anti-mesothelioma potential of capsaicin by observing its cytotoxicity on healthy, immortalized and cancerous cells of mesothelium in vitro and how this potential be affected by lowered Cyclin E levels, a key regulator of G1/S transition of cell cycle. For this purpose, we determined and compared the IC50 values of capsaicin in both FBS (Fetal Bovine Serum) containing and FBS-deprived medium of each cell population studied. Additionally, we examined the changes in both protein and mRNA levels of caspase-3 upon capsaicin exposure as well as conducted a series of experiments through which the relatively long term effect of capsaicin on the growth rate of the cells was assessed. As a result, the reduced Cyclin E obtained through the absence of FBS in growth medium was found not only to decrease IC50 values for all cell types dramatically (p<0.05) but also to cause a considerable difference between the values determined for cancerous and non-cancerous populations (p<0.05), which had not been observed in regular medium. Moreover, along with the fact that capsaicin exposure did not have an impact on the cell growth in long term in most cases, caspase-3 levels also remained the same when exposed to capsaicin, suggesting a mechanism of cell death independent of caspases.
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- Kim J, Bhagwandin S, Labow DM. Malignant peritoneal mesothelioma: a review. Ann Transl Med [Internet]. 2017;5(11):236–236.
- Available from: http://atm.amegroups.com/article/view/14508/15355
- Emri SA. The Cappadocia mesothelioma epidemic: its influence in Turkey and abroad. Ann Transl Med [Internet]. 2017;5(11):239–239. Available from: http://atm.amegroups.com/article/view/15112/15358
- Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–6.
- Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9.
- Carbone M, Yang H. Mesothelioma: recent highlights. Ann Transl Med [Internet]. 2017;5(11):238–238. Available from: http://atm.amegroups.com/article/view/14824/15357
- Grosso F, Scagliotti GV. Systemic treatment of malignant pleural mesothelioma. Future Oncol [Internet]. 2012;8(3):293–305. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22409465
- Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, et al. Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene. 2010;29(2):285–96.
- Ito K, Nakazato T, Yamato K, Miyakawa Y, Yamada T, Hozumi N, et al. Induction of Apoptosis in Leukemic Cells by Homovanillic Acid Derivative, Capsaicin, through Oxidative Stress: Implication of Phosphorylation of p53 at Ser-15 Residue by Reactive Oxygen Species. Cancer Res. 2004;64(3):1071–8.
- Qian K, Wang G, Cao R, Liu T, Qian G, Guan X, et al. Capsaicin suppresses cell proliferation, induces cell cycle arrest and ROS production in bladder cancer cells through FOXO3a-mediated pathways. Molecules. 2016;21(10).
- Ramos-Torres í, Bort A, Morell C, Rodríguez-Henche N, Díaz-Laviada I. The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget [Internet]. 2016;7(2):1569–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26625315%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4811481
- Huang S-P, Chen J-C, Wu C-C, Chen C-T, Tang N-Y, Ho Y-T, et al. Capsaicin-induced apoptosis in human hepatoma HepG2 cells. Anticancer Res [Internet]. 2009;29(1):165–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19331147
- Bley K, Boorman G, Mohammad B, McKenzie D, Babbar S. A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin. Vol. 40, Toxicologic Pathology. 2012. p. 847–73.
- Morré DJ, Chueh PJ, Morré DM. Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci U S A. 1995;92(March):1831–5.
- Clark R, Lee S. Anticancer Properties of Capsaicin Against Human Cancer. Anticancer Res [Internet]. 2016;36(3):837–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26976969
- Zhang Y, Deng X, Lei T, Yu C, Wang Y, Zhao G, et al. Capsaicin inhibits proliferation and induces apoptosis in osteosarcoma cell lines via the mitogen-activated protein kinase pathway. Oncol Rep. 2017;38(5):2685–96.
- Jin J, Lin G, Huang H, Xu D, Yu H, Ma X, et al. Capsaicin mediates cell cycle arrest and apoptosis in human colon cancer cells via stabilizing and activating p53. Int J Biol Sci. 2014;10(3):285–95.
- Teixeira LK, Reed SI. Cyclin E deregulation and genomic instability. In: Advances in Experimental Medicine and Biology. 2017. p. 527–47.
- Chi XZ, Lee JW, Lee YS, Park IY, Ito Y, Bae SC. Runx3 plays a critical role in restriction-point and defense against cellular transformation. Oncogene. 2017;36(50):6884–94.
- T P A. Pharmacogenomics: The Right Drug to the Right Person. J Clin Med Res [Internet]. 2009; Available from: http://www.jocmr.org/index.php/JOCMR/article/view/207
- Madian AG, Wheeler HE, Jones RB, Dolan ME. Relating human genetic variation to variation in drug responses. Vol. 28, Trends in Genetics. 2012. p. 487–95.
- Chou C-C, Wu Y-C, Wang Y-F, Chou M-J, Kuo S-J, Chen D-R. Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway. Oncol Rep [Internet]. 2009;21(3):665–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19212624
- Burt M, Jagirdar J, Aston C, Rom WN. Normal Human Mesothelial Cells and Mesothelioma Cell Lines Express Insulin-like Growth Factor I and Associated Molecules. Cancer Res. 1993;53(12):2858–64.
- Shukla A, MacPherson MB, Hillegass J, Ramos-Nino ME, Alexeeva V, Vacek PM, et al. Alterations in gene expression in human mesothelial cells correlate with mineral pathogenicity. Am J Respir Cell Mol Biol. 2009;41(1):114–23.
- Rosa A, Deiana M, Casu V, Paccagnini S, Appendino G, Ballero M, et al. Antioxidant activity of capsinoids. J Agric Food Chem. 2002;50(25):7396–401.
- Huang KT, Chen YH, Walker AM. Inaccuracies in MTS assays: Major distorting effects of medium, serum albumin, and fatty acids. Biotechniques. 2004;37(3):406–12.
- Shin DH, Kim OH, Jun HS, Kang MK. Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway. Exp Mol Med. 2008;40(5):486–94.
- Yang F, Zheng J. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Vol. 8, Protein and Cell. 2017. p. 169–77.
- Comertpay S, Pastorino S, Tanji M, Mezzapelle R, Strianese O, Napolitano A, et al. Evaluation of clonal origin of malignant mesothelioma. J Transl Med. 2014;12(1).
- Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles. Vol. 24, Oncogene. 2005. p. 2776–86.
- Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: Does one fit all? Vol. 9, Nature Reviews Molecular Cell Biology. 2008. p. 910–6.
- Vandermeers F, Hubert P, Delvenne P, Mascaux C, Grigoriu B, Burny A, et al. Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma. Clin Cancer Res. 2009;15(8):2818–28.
References
Kim J, Bhagwandin S, Labow DM. Malignant peritoneal mesothelioma: a review. Ann Transl Med [Internet]. 2017;5(11):236–236.
Available from: http://atm.amegroups.com/article/view/14508/15355
Emri SA. The Cappadocia mesothelioma epidemic: its influence in Turkey and abroad. Ann Transl Med [Internet]. 2017;5(11):239–239. Available from: http://atm.amegroups.com/article/view/15112/15358
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022–6.
Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9.
Carbone M, Yang H. Mesothelioma: recent highlights. Ann Transl Med [Internet]. 2017;5(11):238–238. Available from: http://atm.amegroups.com/article/view/14824/15357
Grosso F, Scagliotti GV. Systemic treatment of malignant pleural mesothelioma. Future Oncol [Internet]. 2012;8(3):293–305. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22409465
Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, et al. Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene. 2010;29(2):285–96.
Ito K, Nakazato T, Yamato K, Miyakawa Y, Yamada T, Hozumi N, et al. Induction of Apoptosis in Leukemic Cells by Homovanillic Acid Derivative, Capsaicin, through Oxidative Stress: Implication of Phosphorylation of p53 at Ser-15 Residue by Reactive Oxygen Species. Cancer Res. 2004;64(3):1071–8.
Qian K, Wang G, Cao R, Liu T, Qian G, Guan X, et al. Capsaicin suppresses cell proliferation, induces cell cycle arrest and ROS production in bladder cancer cells through FOXO3a-mediated pathways. Molecules. 2016;21(10).
Ramos-Torres í, Bort A, Morell C, Rodríguez-Henche N, Díaz-Laviada I. The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget [Internet]. 2016;7(2):1569–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26625315%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4811481
Huang S-P, Chen J-C, Wu C-C, Chen C-T, Tang N-Y, Ho Y-T, et al. Capsaicin-induced apoptosis in human hepatoma HepG2 cells. Anticancer Res [Internet]. 2009;29(1):165–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19331147
Bley K, Boorman G, Mohammad B, McKenzie D, Babbar S. A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin. Vol. 40, Toxicologic Pathology. 2012. p. 847–73.
Morré DJ, Chueh PJ, Morré DM. Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci U S A. 1995;92(March):1831–5.
Clark R, Lee S. Anticancer Properties of Capsaicin Against Human Cancer. Anticancer Res [Internet]. 2016;36(3):837–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26976969
Zhang Y, Deng X, Lei T, Yu C, Wang Y, Zhao G, et al. Capsaicin inhibits proliferation and induces apoptosis in osteosarcoma cell lines via the mitogen-activated protein kinase pathway. Oncol Rep. 2017;38(5):2685–96.
Jin J, Lin G, Huang H, Xu D, Yu H, Ma X, et al. Capsaicin mediates cell cycle arrest and apoptosis in human colon cancer cells via stabilizing and activating p53. Int J Biol Sci. 2014;10(3):285–95.
Teixeira LK, Reed SI. Cyclin E deregulation and genomic instability. In: Advances in Experimental Medicine and Biology. 2017. p. 527–47.
Chi XZ, Lee JW, Lee YS, Park IY, Ito Y, Bae SC. Runx3 plays a critical role in restriction-point and defense against cellular transformation. Oncogene. 2017;36(50):6884–94.
T P A. Pharmacogenomics: The Right Drug to the Right Person. J Clin Med Res [Internet]. 2009; Available from: http://www.jocmr.org/index.php/JOCMR/article/view/207
Madian AG, Wheeler HE, Jones RB, Dolan ME. Relating human genetic variation to variation in drug responses. Vol. 28, Trends in Genetics. 2012. p. 487–95.
Chou C-C, Wu Y-C, Wang Y-F, Chou M-J, Kuo S-J, Chen D-R. Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway. Oncol Rep [Internet]. 2009;21(3):665–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19212624
Burt M, Jagirdar J, Aston C, Rom WN. Normal Human Mesothelial Cells and Mesothelioma Cell Lines Express Insulin-like Growth Factor I and Associated Molecules. Cancer Res. 1993;53(12):2858–64.
Shukla A, MacPherson MB, Hillegass J, Ramos-Nino ME, Alexeeva V, Vacek PM, et al. Alterations in gene expression in human mesothelial cells correlate with mineral pathogenicity. Am J Respir Cell Mol Biol. 2009;41(1):114–23.
Rosa A, Deiana M, Casu V, Paccagnini S, Appendino G, Ballero M, et al. Antioxidant activity of capsinoids. J Agric Food Chem. 2002;50(25):7396–401.
Huang KT, Chen YH, Walker AM. Inaccuracies in MTS assays: Major distorting effects of medium, serum albumin, and fatty acids. Biotechniques. 2004;37(3):406–12.
Shin DH, Kim OH, Jun HS, Kang MK. Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway. Exp Mol Med. 2008;40(5):486–94.
Yang F, Zheng J. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Vol. 8, Protein and Cell. 2017. p. 169–77.
Comertpay S, Pastorino S, Tanji M, Mezzapelle R, Strianese O, Napolitano A, et al. Evaluation of clonal origin of malignant mesothelioma. J Transl Med. 2014;12(1).
Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles. Vol. 24, Oncogene. 2005. p. 2776–86.
Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: Does one fit all? Vol. 9, Nature Reviews Molecular Cell Biology. 2008. p. 910–6.
Vandermeers F, Hubert P, Delvenne P, Mascaux C, Grigoriu B, Burny A, et al. Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma. Clin Cancer Res. 2009;15(8):2818–28.