Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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8-Methoxypsoralen Induces Apoptosis by Upregulating p53 and Inhibits Metastasis by Downregulating MMP-2 and MMP-9 in Human Gastric Cancer Cells

  • Eun Kyoung, Choi (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Hae Dong, Kim (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Eun Jung, Park (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Seuk Young, Song (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Tien Thuy, Phan (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Miyoung, Nam (Department of New Drug Development, Chungnam National University) ;
  • Minjung, Kim (Department of New Drug Development, Chungnam National University) ;
  • Dong-Uk, Kim (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Kwang-Lae, Hoe (Department of New Drug Development, Chungnam National University)
  • Received : 2023.01.09
  • Accepted : 2023.01.17
  • Published : 2023.03.01
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Abstract

Furanocoumarin 8-methoxypsoralen (8-MOP) is the parent compound that naturally occurs in traditional medicinal plants used historically. 8-MOP has been employed as a photochemotherapeutic component of Psoralen + Ultraviolet A (PUVA) therapy for the treatment of vitiligo and psoriasis. Although the role of 8-MOP in PUVA therapy has been studied, little is known about the effects of 8-MOP alone on human gastric cancer cells. In this study, we observed anti-proliferative effect of 8-MOP in several human cancer cell lines. Among these, the human gastric cancer cell line SNU1 is the most sensitive to 8-MOP. 8-MOP treated SNU1 cells showed G1-arrest by upregulating p53 and apoptosis by activating caspase-3 in a dose-dependent manner, which was confirmed by loss-of-function analysis through the knockdown of p53-siRNA and inhibition of apoptosis by Z-VAD-FMK. Moreover, 8-MOP-induced apoptosis is not associated with autophagy or necrosis. The signaling pathway responsible for the effect of 8-MOP on SNU1 cells was confirmed to be related to phosphorylated PI3K, ERK2, and STAT3. In contrast, 8-MOP treatment decreased the expression of the typical metastasis-related proteins MMP-2, MMP-9, and Snail in a p53-independent manner. In accordance with the serendipitous findings, treatment with 8-MOP decreased the wound healing, migration, and invasion ability of cells in a dose-dependent manner. In addition, combination treatment with 8-MOP and gemcitabine was effective at the lowest concentrations. Overall, our findings indicate that oral 8-MOP has the potential to treat early human gastric cancer, with fewer side effects.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT of Korea (NRF-2017M3A9B5060881, NRF-2017M3C9A5028693, and NRF-2017M3A9B5060880). Human resources were supported by the Chungnam National University and the Korea Research Institute of Bioscience and Biotechnology (KRIBB).

References

  1. Arabzadeh, A., Bathaie, S. Z., Farsam, H., Amanlou, M., Saboury, A. A., Shockravi, A. and Moosavi-Movahedi, A. A. (2002) Studies on mechanism of 8-methoxypsoralen-DNA interaction in the dark. Int. J. Pharm. 237, 47-55. https://doi.org/10.1016/S0378-5173(02)00020-0
  2. Bartosova, J., Kuzelova, K., Pluskalova, M., Marinov, I., Halada, P. and Gasova, Z. (2006) UVA-activated 8-methoxypsoralen (PUVA) causes G2/M cell cycle arrest in Karpas 299 T-lymphoma cells. J. Photochem. Photobiol. B 85, 39-48. https://doi.org/10.1016/j.jphotobiol.2006.04.002
  3. Busuttil, R. A., Zapparoli, G. V., Haupt, S., Fennell, C., Wong, S. Q., Pang, J. M., Takeno, E. A., Mitchell, C., Di Costanzo, N., Fox, S., Haupt, Y., Dobrovic, A. and Boussioutas, A. (2014) Role of p53 in the progression of gastric cancer. Oncotarget 5, 12016-12026. https://doi.org/10.18632/oncotarget.2434
  4. Canton, M., Caffieri, S., Dall'Acqua, F. and Di Lisa, F. (2002) PUVA-induced apoptosis involves mitochondrial dysfunction caused by the opening of the permeability transition pore. FEBS Lett. 522, 168-172. https://doi.org/10.1016/S0014-5793(02)02926-5
  5. Fenoglio-Preiser, C. M., Wang, J., Stemmermann, G. N. and Noffsinger, A. (2003) TP53 and gastric carcinoma: a review. Hum. Mutat. 21, 258-70. https://doi.org/10.1002/humu.10180
  6. Gabbert, H. E., Muller, W., Schneiders, A., Meier, S. and Hommel, G. (1995) The relationship of p53 expression to the prognosis of 418 patients with gastric carcinoma. Cancer 76, 720-726. https://doi.org/10.1002/1097-0142(19950901)76:5<720::AID-CNCR2820760503>3.0.CO;2-E
  7. Gialeli, C., Theocharis, A. D. and Karamanos, N. K. (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278, 16-27. https://doi.org/10.1111/j.1742-4658.2010.07919.x
  8. Hearst, J. E., Isaacs, S. T., Kanne, D., Rapoport, H. and Straub, K. (1984) The reaction of the psoralens with deoxyribonucleic acid. Q. Rev. Biophys. 17, 1-44. https://doi.org/10.1017/S0033583500005242
  9. Henseler, T., Wolff, K., Honigsmann, H. and Christophers, E. (1981) Oral 8-methoxypsoralen photochemotherapy of psoriasis. The European PUVA study: a cooperative study among 18 European centres. Lancet 1, 853-857. https://doi.org/10.1016/S0140-6736(81)92137-1
  10. Imazeki, F., Omata, M., Nose, H., Ohto, M. and Isono, K. (1992) p53 gene mutations in gastric and esophageal cancers. Gastroenterology 103, 892-896. https://doi.org/10.1016/0016-5085(92)90022-q
  11. Li, H. C., Cao, D. C., Liu, Y., Hou, Y. F., Wu, J., Lu, J. S., Di, G. H., Liu, G., Li, F. M., Ou, Z. L., Jie, C., Shen, Z. Z. and Shao, Z. M. (2004) Prognostic value of matrix metalloproteinases (MMP-2 and MMP9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res.Treat. 88, 75-85. https://doi.org/10.1007/s10549-004-1200-8
  12. Li, J., Zhang, Z., Qiu, J. and Huang, X. (2021) 8-Methoxypsoralen has anti-inflammatory and antioxidant roles in osteoarthritis through SIRT1/NF-κB pathway. Front Pharmacol. 12, 692424.
  13. Liu, Z., Lu, Y., Lebwohl, M. and Wei, H. (1999) PUVA (8-methoxypsoralen plus ultraviolet A) induces the formation of 8-hydroxy-2'-deoxyguanosine and DNA fragmentation in calf thymus DNA and human epidermoid carcinoma cells. Free Radic. Biol. Med. 27, 127-133. https://doi.org/10.1016/S0891-5849(99)00058-1
  14. Lund, B., Kristjansen, P. E. and Hansen, H. H. (1993) Clinical and preclinical activity of 2',2'-difluorodeoxycytidine (gemcitabine). Cancer Treat. Rev. 19, 45-55.
  15. March, K. L., Patton, B. L., Wilensky, R. L. and Hathaway, D. R. (1993) 8-Methoxypsoralen and longwave ultraviolet irradiation are a novel antiproliferative combination for vascular smooth muscle. Circulation 87, 184-191. https://doi.org/10.1161/01.CIR.87.1.184
  16. Melski, J. W., Tanenbaum, L., Parrish, J. A., Fitzpatrick, T. B. and Bleich, H. L. (1977) Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. J. Invest. Dermatol. 68, 328-335. https://doi.org/10.1111/1523-1747.ep12496022
  17. Panno, M. L., Giordano, F., Palma, M. G., Bartella, V., Rago, V., Maggiolini, M., Sisci, D., Lanzino, M., De Amicis, F. and Ando, S. (2009) Evidence that bergapten, independently of its photoactivation, enhances p53 gene expression and induces apoptosis in human breast cancer cells. Curr. Cancer Drug Targets 9, 469-481. https://doi.org/10.2174/156800909788486786
  18. Parrish, J. A., Fitzpatrick, T. B., Tanenbaum, L. and Pathak, M. A. (1974) Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N. Eng. J. Med. 291, 1207-1211. https://doi.org/10.1056/NEJM197412052912301
  19. Pathak, M. A. and Fitzpatrick, T. B. (1992) The evolution of photochemotherapy with psoralens and UVA (PUVA): 2000 BC to 1992 AD. J. Photochem. Photobiol. B 14, 3-22. https://doi.org/10.1016/1011-1344(92)85080-E
  20. Peng, Y., Liu, W., Xiong, J., Gui, H. Y., Feng, X. M., Chen, R. N., Hu, G. and Yang, J. (2012) Down regulation of differentiated embryonic chondrocytes 1 (DEC1) is involved in 8-methoxypsoralen-induced apoptosis in HepG2 cells. Toxicology 301, 58-65. https://doi.org/10.1016/j.tox.2012.06.022
  21. Santamaria, A. B., Davis, D. W., Nghiem, D. X., McConkey, D. J., Ullrich, S. E., Kapoor, M., Lozano, G. and Ananthaswamy, H. N. (2002) p53 and Fas ligand are required for psoralen and UVA-induced apoptosis in mouse epidermal cells. Cell Death Differ. 9, 549-560. https://doi.org/10.1038/sj/cdd/4401007
  22. Shin, N. R., Jeong, E. H., Choi, C. I., Moon, H. J., Kwon, C. H., Chu, I. S., Kim, G. H., Jeon, T. Y., Kim, D. H., Lee, J. H. and Park, D. Y. (2012) Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer. BMC Cancer 12, 521.
  23. Stadler, K., Frey, B., Munoz, L. E., Finzel, S., Rech, J., Fietkau, R., Herrmann, M., Hueber, A. and Gaipl, U. S. (2009) Photopheresis with UV-A light and 8-methoxypsoralen leads to cell death and to release of blebs with anti-inflammatory phenotype in activated and non-activated lymphocytes. Biochem. Biophys. Res. Commun. 386, 71-76. https://doi.org/10.1016/j.bbrc.2009.05.130
  24. Takashima, A., Yamada, Y., Nakajima, T. E., Kato, K., Hamaguchi, T. and Shimada, Y. (2009) Standard first-line chemotherapy for metastatic gastric cancer in Japan has met the global standard: evidence from recent phase III trials. Gastroint. Cancer Res. 3, 239-244.
  25. Talvensaari-Mattila, A., Paakko, P., Hoyhtya, M., Blanco-Sequeiros, G. and Turpeenniemi-Hujanen, T. (1998) Matrix metalloproteinase-2 immunoreactive protein: a marker of aggressiveness in breast carcinoma. Cancer 83, 1153-1162. https://doi.org/10.1002/(SICI)1097-0142(19980915)83:6<1153::AID-CNCR14>3.0.CO;2-4
  26. Vogelstein, B., Lane, D. and Levine, A. J. (2000) Surfing the p53 network. Nature 408, 307-310. https://doi.org/10.1038/35042675
  27. Wolff, K. W., Fitzpatrick, T. B., Parrish, J. A., Gschnait, F., Gilchrest, B., Honigsmann, H., Pathak, M. A. and Tannenbaum, L. (1976) Photochemotherapy for psoriasis with orally administered methoxsalen. Arch. Dermatol. 112, 943-950. https://doi.org/10.1001/archderm.1976.01630310005001
  28. Xia, W., Gooden, D., Liu, L., Zhao, S., Soderblom, E. J., Toone, E. J., Beyer, W. F., Jr., Walder, H. and Spector, N. L. (2014) Photoactivated psoralen binds the ErbB2 catalytic kinase domain, blocking ErbB2 signaling and triggering tumor cell apoptosis. PLoS One 9, e88983.
  29. Xiong, J., Yang, H., Luo, W., Shan, E., Liu, J., Zhang, F., Xi, T. and Yang, J. (2016) The anti-metastatic effect of 8-MOP on hepatocellular carcinoma is potentiated by the down-regulation of bHLH transcription factor DEC1. Pharmacol. Res. 105, 121-133. https://doi.org/10.1016/j.phrs.2016.01.025