Abstract
A new ligand BTCP and its iridium(III) complex [Ir(ppy)2(BTCP)]PF6 (Ir-1) were synthesized and characterized by elemental analysis, ESI–MS, IR, 1H NMR and 13C NMR. The cytotoxic activity in vitro of the ligand and its complex against SGC-7901, HeLa, HOS, PC-12, BEL-7402, MG-63, SiHa, A549, HepG2 and normal cell LO2 were evaluated by MTT method [MTT = (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)]. The apoptosis was assayed with AO/EB and Hoechst 33258 staining methods. The reactive oxygen species (ROS), mitochondrial membrane potential, autophagy and cell invasion were studied under fluorescent microscope. The expression of caspases and Bcl-2 family proteins were investigated by western blot. The IC50 values of complex toward SGC-7901, BEL-7402 and MG-63 cells are 3.9 ± 0.5, 5.4 ± 1.2 and 4.2 ± 0.6 µM. The complex can increase the levels of ROS, and induce a decrease in the mitochondrial membrane potential. Ir-1 inhibits the cell growth at G0/G1 phase in SGC-7901 cells, and the complex can induce both autophagy and apoptosis and inhibit the cell invasion. And the complex induces apoptosis through a ROS-mediated mitochondrial dysfunction pathway.
Similar content being viewed by others
References
Aragon-Ching BJ, Dahut WL (2009) Update Cancer Ther 3:182–188
De Martel C, Ferlay J, Franceschi S (2012) Lancet Oncol 13:607–615
Kelland L (2007) Nat Rev Cancer 7:573–584
Harlos M, Ott I, Gust R, Alborzinia H, Wölfl S, Kromm A, Sheldrick WS (2008) J Med Chem 51:3924–3933
Boff B, Gaiddon C, Pfeffer M (2013) Inorg Chem 52:2705–2715
Haas KL, Franz KJ (2009) Chem Rev 109:4921–4960
Goswami TK, Chakravarthi BVSK, Roy M, Karande AA, Chakravarty AR (2011) Inorg Chem 50:8452–8464
Zhang C, Zeng CC, Lai SH, Xing DG, Li W, Han BJ, Liu YJ (2016) Polyhedron 106:115–124
Lai SH, Li W, Yao JH, Han BJ, Jiang GB, Zhang C, Liu YJ (2016) J Photochem Photobiol B Biol 158:39–48
Rijt SHV, Mukherjee A, Pizarro AM, Sadler PJ (2010) J Med Chem 53:840–849
Louie MW, Choi AWT, Liu HW, Chan BTN, Lo KK (2012) Organometallics 31:5844–5855
Liu Z, Habtemariam A, Pizarro AM, Fletcher SA, Kisova A, Vrana O, Salassa L, Bruijnincx PCA, Clarkson GJ, Brabec V, Sadler PJ (2011) J Med Chem 54:3011–3026
Liu Z, Salassa L, Habtemariam A, Pizarro AM, Clarkson GJ, Sadler PJ (2011) Inorg Chem 50:5777–5783
Huang HY, Yang L, Zhang PY, Qiu KQ, Huang JJ, Chen Y, Diao JJ, Liu JK, Ji LN, Long JG, Chao H (2016) Biomaterials 83:321–331
Wu ZZ, Mu JJ, Wang Q, Chen X, Jensen L, Yi CQ, Li MJ (2015) J Organomet Chem 791:175–182
Thangavel S, Paulpandi M, Friedrich HB, Murugan K, Kalva S, Skelton AA (2016) J Inorg Biochem 159:50–61
Almodares Z, Lucas SJ, Crossley BD, Basri AM, Pask CM, Hebden AJ, Phillips RM, McGowan PC (2014) Inorg Chem 53:727–736
Mukhopadhyay S, Gupta RK, Paitandi RP, Rana NK, Sharma G, Koch B, Rana LK, Hundal MS, Pandey DS (2015) Organometallics 34:4491–4506
Bach C, Willner H, Aubke F, Wang CQ, Rettig SJ, Trotter J (1996) Angew Chem Int Ed 35:1974–1976
Li Y, Tan CP, Zhang W, He L, Ji LN, Mao ZW (2015) Biomaterials 39:95–104
Amouri H, Moussa J, Renfrew AK, Dyson PJ, Rager MN, Chamoreau LM (2010) Angew Chem Int Ed 49:7530–7533
Xiong K, Chen Y, Yang CO, Guan RL, Ji LN, Chao H (2016) Biochimie 125:186–194
Li SPY, Lau CTS, Louie MW, Lam YW, Cheng SH, Lo KKW (2013) Biomaterials 34:7519–7532
Cao R, Jia JL, Ma XC, Zhou M, Fei H (2013) J Med Chem 56:3636–3644
Li GY, Lin Q, Sun LL, Feng CS, Zhang PY, Yu B, Chen Y, Wen Y, Wang H, Ji LN, Chao H (2015) Biomaterials 53:285–295
Chen Y, Xu WC, Zuo JR, Ji LN, Chao H (2015) J Mater Chem B 3:3306–3314
McBride HM, Neuspiel M, Wasiak S (2006) Curr Biol 16:R551–R560
Henze K, Martin W (2002) Nature 426:127–128
Paw W, Eisenberg R (1997) Inorg Chem 36:2287–2293
Sprouse S, King KA, Spellane PJ, Watts RJ (1984) J Am Chem Soc 106:6647–6653
Mosmann T (1983) J Immunol Methods 65:55–63
Lo KK, Lee TK, Lau JS, Poon WL, Cheng SH (2008) Inorg Chem 47:200–208
He L, Liao SY, Tan CP, Lu YY, Xu CX, Ji LN, Mao ZW (2014) Chem Commun 50:5611–5614
Li SPY, Lau CTS, Louie MW, Lam YW, Cheng SH, Lo KKW (2013) Biomaterials 34:7519–7532
Hickman JA (1992) Cancer Metastasis Rev 11:121–139
Li W, Nie S, Yu Q, Xie M (2009) J Agr Chem 57:6685–6691
Li GY, Du KJ, Wang JQ, Liang JW, Kou JF, Hou XJ, Ji LN, Chao H (2013) J Inorg Biochem 119:43–53
Alapetite C, Wachter T, Sage E, Moustacchi E (1996) Int J Radiat Biol 69:359–369
Leung CW, Hong Y, Chen S, Zhao E, Lam JW, Tang BZ (2013) J Am Soc Chem 135:63–65
Liu SH, Zhao JH, Deng KK, Wu Y, Zhu JW, Liu QH, Xua HH, Wu HF, Li XY, Wang JW, Guo QF (2015) Spectrochim Acta A 140:202–209
Trachootham D, Alexandre J, Huang P (2009) Nat Rev Drug Discov 8:579–591
Wrona M, Patel K, Wardman P (2005) Free Radic Biol Med 38:262–270
Shapiro GI, Harper JW (1999) J Clin Invest 104:1645–1653
Wang D, Lippard SJ (2005) Nat Rev Drug Discov 4:307–320
He CC, Klionsky DJ (2009) Annu Rev Genet 43:67–93
Shintani T, Klionsky DJ (2004) Science 306:990–995
Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) Nat Rev Cancer 5:726–734
Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, Gelovani J, Krishnan S, Guha S, Aggarwal BB (2010) Int J Cancer 127:257–268
Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) EMBO J 19:5720–5728
Danial NN, Korsmeyer SJ (2004) Cell 116:205–219
Chambers AF, Groom AC, MacDonald IC (2002) Nat Rev Cancer 2:563–572
Acknowledgements
This work was supported by the Natural Science foundation of Guangdong Province (No. 2016A030313728), the High-Level Personnel Project of Guangdong Province in 2013 and the Joint Nature Science Fund of the Department of Science and Technology and the First Affiliated Hospital of Guangdong Pharmaceutical University (No GYFYLH201315) and Project of Innovation for Enhancing Guangdong Pharmaceutical University, Provincial Experimental Teaching Demonstration Center of Chemistry and Chemical Engineering.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zhang, C., Lai, SH., Zeng, CC. et al. The induction of apoptosis in SGC-7901 cells through the ROS-mediated mitochondrial dysfunction pathway by a Ir(III) complex. J Biol Inorg Chem 21, 1047–1060 (2016). https://doi.org/10.1007/s00775-016-1401-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-016-1401-8