Abstract
Photodynamic therapy (PDT) represents a rapidly developing alternative treatment for various types of cancers. Although considered highly effective, cancer cells can exploit various mechanisms, including the upregulation of apoptosis inhibitors, to overcome the cytotoxic effect of PDT. Survivin, a member of the inhibitor of apoptosis protein family, is known to play a critical role in cancer progression and therapeutic resistance and therefore represents a potential therapeutic target. The aim of this study was to investigate whether YM155, a small molecule inhibitor of survivin expression, can potentiate the cytotoxic effect of hypericin-mediated PDT (HY-PDT). Accordingly, two cell lines resistant to HY-PDT, HT-29 (colorectal adenocarcinoma) and A549 (lung adenocarcinoma), were treated either with HY-PDT alone or in combination with YM155. The efficacy of different treatment regimens was assessed by MTT assay, flow cytometry analysis of metabolic activity, viability, phosphatidylserine externalisation, mitochondrial membrane potential and caspase-3 activity and immunoblotting for the cleavage of poly (ADP-ribose) polymerase (PARP). Here we show for the first time that the repression of survivin expression by YM155 is effective in sensitizing HT-29 and A549 cells to HY-PDT, as measured by the decrease in cell viability and induction of apoptosis. Combined treatment with hypericin and YM155 led to a more severe dissipation of the mitochondrial membrane potential and caused an increase in caspase-3 activation and subsequent PARP cleavage. Our results demonstrate that the repression of survivin expression by YM155 potentially represents a novel alternative strategy to increase the efficacy of HY-PDT in cancer cells that are otherwise weakly responsive or non-responsive to treatment.
Similar content being viewed by others
References
D. Hanahan and R. A. Weinberg, Hallmarks of cancer: the next generation, Cell, 2011, 1445, 646–674.
T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Korbelik, J. Moan and Q. Peng, Photodynamic therapy, J. Natl. Cancer Inst., 1998, 9012, 889–905.
S. Onoue, Y. Seto, M. Ochi, R. Inoue, H. Ito, T. Hatano and S. Yamada, In vitro photochemical and phototoxicological characterization of major constituents in St. John’s Wort (Hypericum perforatum) extracts, Phytochemistry, 2011, 7214–15, 1814–1820.
C. Bernal, A. O. Ribeiro, G. P. Andrade and J. R. Perussi, Photodynamic efficiency of hypericin compared with chlorin and hematoporphyrin derivatives in HEp-2 and Vero epithelial cell lines, Photodiagn. Photodyn. Ther., 2015, 122, 176–185.
A. Karioti and A. R. Bilia, Hypericins as potential leads for new therapeutics, Int. J. Mol. Sci., 2010, 112, 562–594.
A. Casas, G. Di Venosa, T. Hasan and B. Al, Mechanisms of resistance to photodynamic therapy, Curr. Med. Chem., 2011, 1816, 2486–2515.
D. C. Altieri, Survivin, cancer networks and pathway-directed drug discovery, Nat. Rev. Cancer, 2008, 81, 61–70.
M. S. Coumar, F. Y. Tsai, J. R. Kanwar, S. Sarvagalla and C. H. Cheung, Treat cancers by targeting survivin: just a dream or future reality?, Cancer Treat. Rev., 2013, 397, 802–811.
Q. Cheng, X. Ling, A. Haller, T. Nakahara, K. Yamanaka, A. Kita, H. Koutoku, M. Takeuchi, M. G. Brattain and F. Li, Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter, Int. J. Biochem. Mol. Biol., 2012, 32, 179–197.
T. Nakahara, A. Kita, K. Yamanaka, M. Mori, N. Amino, M. Takeuchi, F. Tominaga, I. Kinoyama, A. Matsuhisa, M. Kudou and M. Sasamata, Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models, Cancer Sci., 2011, 1023, 614–621.
T. Iwasa, I. Okamoto, K. Takezawa, K. Yamanaka, T. Nakahara, A. Kita, H. Koutoku, M. Sasamata, E. Hatashita, Y. Yamada, K. Kuwata, M. Fukuoka and K. Nakagawa, Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs, Br. J. Cancer, 2010, 1031, 36–42.
J. Chen, C. A. Pise-Masison, J. H. Shih, J. C. Morris, J. E. Janik, K. C. Conlon, A. Keating and T. A. Waldmann, Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia, Blood, 2013, 12111, 2029–2037.
M. Pennati, S. Sbarra, M. De Cesare, A. Lopergolo, S. L. Locatelli, E. Campi, M. G. Daidone, C. Carlo-Stella, A. M. Gianni and N. Zaffaroni, YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK- and CHOP-mediated DR5 upregulation, Int. J. Cancer, 2015, 1362, 299–309.
T. C. Chou and P. Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors, Adv. Enzyme Regul., 1984, 22, 27–55.
J. Mikes, J. Kleban, V. Sackova, V. Horvath, E. Jamborova, A. Vaculova, A. Kozubik, J. Hofmanova and P. Fedorocko, Necrosis predominates in the cell death of human colon adenocarcinoma HT-29 cells treated under variable conditions of photodynamic therapy with hypericin, Photochem. Photobiol. Sci., 2007, 67, 758–766.
Y. Oh, M. Swierczewska, T. H. Kim, S. M. Lim, H. N. Eom, J. H. Park, D. H. Na, K. Kim, K. C. Lee, M. G. Pomper and S. Lee, Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors, J. Controlled Release, 2015, 220Pt B, 671–681.
A. Y. Kim, J. H. Kwak, N. K. Je, Y. H. Lee and Y. S. Jung, Epithelial-mesenchymal Transition is Associated with Acquired Resistance to 5-Fluorocuracil in HT-29 Colon Cancer Cells, Toxicol. Res., 2015, 312, 151–156.
G. Yang, O. Jiang, D. Ling, X. Jiang, P. Yuan, G. Zeng, J. Zhu, J. Tian, Y. Weng and D. Wu, MicroRNA-522 reverses drug resistance of doxorubicin-induced HT29 colon cancer cell by targeting ABCB5, Mol. Med. Rep., 2015, 123, 3930–3936.
A. Gines, S. Bystrup, V. Ruiz de Porras, C. Guardia, E. Musulen, A. Martinez-Cardus, J. L. Manzano, L. Layos, A. Abad, E. Martinez-Balibrea, PKM2 Subcellular Localization Is Involved in Oxaliplatin Resistance Acquisition in HT29 Human Colorectal Cancer Cell Lines, PLoS One, 2015, 105, e0123830.
M. Zhao, H. Li, X. Bu, C. Lei, Q. Fang and Z. Hu, Quantitative Proteomic Analysis of Cellular Resistance to the Nanoparticle Abraxane, ACS Nano, 2015, 910, 10099–10112.
H. Li, P. Zhang, X. Sun, Y. Sun, C. Shi, H. Liu and X. Liu, MicroRNA-181a regulates epithelial-mesenchymal transition by targeting PTEN in drug-resistant lung adenocarcinoma cells, Int. J. Oncol., 2015, 474, 1379–1392.
T. Kwon, J. K. Rho, J. C. Lee, Y. H. Park, H. J. Shin, S. Cho, Y. K. Kang, B. Y. Kim, D. Y. Yoon and D. Y. Yu, An important role for peroxiredoxin II in survival of A549 lung cancer cells resistant to gefitinib, Exp. Mol. Med., 2015, 47, e165.
W. H. Chiu, W. C. Su, C. L. Li, C. L. Chen and C. F. Lin, An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells, Oncotarget, 2015, 624, 20513–20524.
L. Mikesova, J. Mikes, J. Koval, K. Gyuraszova, L. Culka, J. Vargova, B. Valekova and P. Fedorocko, Conjunction of glutathione level, NAD(P)H/FAD redox status and hypericin content as a potential factor affecting colon cancer cell resistance to photodynamic therapy with hypericin, Photodiagn. Photodyn. Ther., 2013, 104, 470–483.
P. Solar, I. Cavarga, J. Hofmanova, M. Cekanova-Figurova, P. Miskovsky, P. Brezani, G. Hrckova, A. Kozubik and P. Fedorocko, Effect of acetazolamide on hypericin photocytotoxicity, Planta Med., 2002, 687, 658–660.
A. Ferrario, N. Rucker, S. Wong, M. Luna and C. J. Gomer, Survivin, a member of the inhibitor of apoptosis family, is induced by photodynamic therapy and is a target for improving treatment response, Cancer Res., 2007, 6710, 4989–4995.
R. Bhowmick and A. W. Girotti, Cytoprotective signaling associated with nitric oxide upregulation in tumor cells subjected to photodynamic therapy-like oxidative stress, Free Radical Biol. Med., 2013, 57, 39–48.
I. S. Cogno, N. B. Vittar, M. J. Lamberti and V. A. Rivarola, Optimization of photodynamic therapy response by survivin gene knockdown in human metastatic breast cancer T47D cells, J. Photochem. Photobiol., B, 2011, 1043, 434–443.
M. Carmena, M. Wheelock, H. Funabiki and W. C. Earnshaw, The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis, Nat. Rev. Mol. Cell Biol., 2012, 1312, 789–803.
E. V. Froehlich, B. Rinner, A. J. Deutsch, K. Meditz, H. Knausz, K. Troppan, S. Scheipl, C. Wibmer, A. Leithner, B. Liegl and B. Lohberger, Examination of survivin expression in 50 chordoma specimens–A histological and in vitro study, J. Orthop. Res., 2015, 335, 771–778.
D. Dai, Y. Liang, Z. Xie, J. Fu, Y. Zhang and Z. Zhang, Survivin deficiency induces apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells, Oncol. Rep., 2012, 273, 621–627.
T. Wang, J. Wei, X. Qian, Y. Ding, L. Yu and B. Liu, Gambogic acid, a potent inhibitor of survivin, reverses docetaxel resistance in gastric cancer cells, Cancer Lett., 2008, 2622, 214–222.
M. Blank, M. Mandel, Y. Keisari, D. Meruelo and G. Lavie, Enhanced ubiquitinylation of heat shock protein 90 as a potential mechanism for mitotic cell death in cancer cells induced with hypericin, Cancer Res., 2003, 6323, 8241–8247.
A. Vantieghem, Y. Xu, Z. Assefa, J. Piette, J. R. Vandenheede, W. Merlevede, P. A. De Witte and P. Agostinis, Phosphorylation of Bcl-2 in G2/M phase-arrested cells following photodynamic therapy with hypericin involves a CDK1-mediated signal and delays the onset of apoptosis, J. Biol. Chem., 2002, 27740, 37718–37731.
X. Wang, Y. Guo, S. Yang, C. Wang, X. Fu, J. Wang, Y. Mao, J. Zhang and Y. Li, Cellular and molecular mechanisms of photodynamic hypericin therapy for nasopharyngeal carcinoma cells, J. Pharmacol. Exp. Ther., 2010, 3343, 847–853.
B. Krammer and T. Verwanger, Molecular response to hypericin-induced photodamage, Curr. Med. Chem., 2012, 196, 793–798.
S. Fulda and D. Kogel, Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy, Oncogene, 2015, 3440, 5105–5113.
R. J. Kelly, A. Lopez-Chavez, D. Citrin, J. E. Janik and J. C. Morris, Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin, Mol. Cancer, 2011, 10, 35.
Y. Yu, X. Zhao, Y. Zhang, Y. Kang, J. Wang and Y. Liu, Antitumor activity of YM155, a selective survivin suppressant, in combination with cisplatin in hepatoblastoma, Oncol. Rep., 2015, 341, 407–414.
R. Mir, E. Stanzani, F. Martinez-Soler, A. Villanueva, A. Vidal, E. Condom, J. Ponce, J. Gil, A. Tortosa, P. Gimenez-Bonafe, YM155 sensitizes ovarian cancer cells to cisplatin inducing apoptosis and tumor regression, Gynecol. Oncol., 2014, 1321, 211–220.
H. Liang, L. Zhang, R. Xu and X. L. Ju, Silencing of survivin using YM155 induces apoptosis and chemosensitization in neuroblastomas cells, Rev. Eur. Sci. Med. Pharmacol., 2013, 1721, 2909–2915.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gyurászová, K., Mikeš, J., Halaburková, A. et al. YM155, a small molecule inhibitor of survivin expression, sensitizes cancer cells to hypericin-mediated photodynamic therapy. Photochem Photobiol Sci 15, 812–821 (2016). https://doi.org/10.1039/c5pp00438a
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1039/c5pp00438a