Berberine enhances the activity of Sunitinib by targeting telomere G-quadruplex

doi:10.5246/jcps.2019.05.029

Abstract

Abstract:

G-quadruplexes are stable secondary structures formed with guanine rich sequences, which are widely distributed in genome. Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells. However, the feasibility of G-quadruplex structures as drug targets needs to be validated. In this study, Sunitinib, an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex. The stabilization was further enhanced by the combined usage with Berberine, an isoquinoline alkaloid. Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex. The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentageof apoptotic cells reaching about 70%. The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells. This study suggested that more clinic drugs could work by targeting G-quadruplex structures.

Key words: Telomere G-quadruplex, Sunitinib, Berberine, Synergistic effects

CLC Number:

R962.1

Supporting:

Table S1. DNA sequences used in the FRET melting assay

Figure S1 The cytotoxic effect on A549 cancer cells of sunitinib or berberine. The cells were treated with sunitinib for 24 h or 48 h. The cells were treated with berberine for 48 h.

Table S2. The combination effects of berberine and sunitinib on A549 cancer cells.

Haitao Hou, Zibing Song, Jieqin Ding, Dengguo Wei, Sheng Hu, Qianqian Zhai, Xiali Yue. Berberine enhances the activity of Sunitinib by targeting telomere G-quadruplex[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(5): 289-297.

References

[1] Hänsel-Hertsch, R.; Di Antonio, M.; Balasubramanian, S. DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat. Rev. Mol. Cell Biol. 2017, 18, 279-284.

[2] Rhodes, D.; Lipps, H.J. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res. 2015, 43, 8627-8637.

[3] Balasubramanian, S.; Hurley, L.H.; Neidle, S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat. Rev. Drug Discov. 2011, 10, 261-275.

[4] Lam, E.Y.; Beraldi, D.; Tannahill, D.; Balasubramanian, S. G-quadruplex structures are stable and detectable in human genomic DNA. Nat. Commun. 2013, 4, 1796.

[5] Xu, Y.; Komiyama, M. Evidence for G-quadruplex DNA in human cells. Chembiochem. 2013, 14, 927-928.

[6] Read, M.; Harrison, R.J.; Romagnoli, B.; Tanious, F.A.; Gowan, S.H.; Reszka, A.P.; Wilson, W.D.; Kelland, L.R.; Neidle, S. Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc. Natl. Acad. Sci. USA. 2001, 98, 4844-4849.

[7] Reed, J.E.; Arnal, A.A.; Neidle, S.; Vilar, R. Stabilization of G-quadruplex DNA and inhibition of telomerase activity by square-planar nickel(II) complexes. J. Am. Chem. Soc. 2006, 128, 5992-5993.

[8] de Lange, T. How telomeres solve the end-protection problem. Science. 2009, 326, 948-952.

[9] O’Sullivan, R.J.; Karlseder, J. Telomeres: protecting chromosomes against genome instability. Nat. Rev. Mol. Cell Biol. 2010, 11, 171-181.

[10] Chaires, J.B. Human telomeric G-quadruplex: thermodynamic and kinetic studies of telomeric quadruplex stability. FEBS J. 2010, 277, 1098-1106.

[11] Phan, A.T. Human telomeric G-quadruplex: structures of DNA and RNA sequences. FEBS J. 2010, 277, 1107-1117.

[12] Neidle, S.; Parkinson, G.N. The structure of telomeric DNA. Curr. Opin. Struct. Biol. 2003, 13, 275-283.

[13] Zhao, C.Q.; Wu, L.; Ren, J.S.; Xu, Y.; Qu, X.G. Targeting human telomeric higher-order DNA: dimeric G-quadruplex units serve as preferred binding site. J. Am. Chem. Soc. 2013, 135, 18786-18789.

[14] Sun, D.; Thompson, B.; Cathers, B.E.; Salazar, M.; Kerwin, S.M.; Trent, J.O.; Jenkins, T.C.; Neidle, S.; Hurley, L.H. Inhibition of human telomerase by a G-quadruplex-interactive compound. J. Med. Chem. 1997, 40, 2113-2116.

[15] Burger, A.M.; Dai, F.P.; Schultes, C.M.; Reszka, A.P.; Moore, M.J.; Double, J.A.; Neidle, S. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res. 2005, 65, 1489-1496.

[16] Neidle, S.; Parkinson, G. Telomere maintenance as a target for anticancer drug discovery. Nat. Rev. Drug Discov. 2002, 1, 383-393.

[17] Fujita, T.; Hirayama, T.; Ishii, D.; Matsumoto, K.; Yoshida, K.; Iwamura, M. Efficacy and safety of sunitinib in elderly patients with advanced renal cell carcinoma. Mol. Clin. Oncol. 2018, 9, 394-398.

[18] Liman, A.D.; Passero, V.A.; Liman, A.K.; Shields, J. A rare case of sunitinib-induced rhabdomyolysis in renal cell carcinoma. Case Rep. Oncol. Med. 2018, 2018, 3808523.

[19] Pozzari, M.; Maisonneuve, P.; Spada, F.; Berruti, A.; Amoroso, V.; Cella, C.A.; Laffi, A.; Pellicori, S.; Bertani, E.; Fazio, N. Systemic therapies in patients with advanced well-differentiated pancreatic neuroendocrine tumors (PanNETs): When cytoreduction is the aim. A critical review with meta-analysis. Cancer Treat. Rev. 2018, 71, 39-46.

[20] Sato, K.; Toyoshima, Y.; Moriyama, S.; Endo, Y.; Ito, T.; Ohki, E. Real-world use of sunitinib in Japanese patients with pancreatic neuroendocrine tumors: results from a post-marketing surveillance study. Cancer Chemother. Pharmacol. 2019, 83, 201-207.

[21] Manir, K.S.; Banerjee, D.; Bhowmick, R.; Roy, C. Sunitinib-induced acute severe hypothyroidism in a case of metastatic gastrointestinal stromal tumor: A case report. J. Cancer Res. Ther. 2018, 14, S818-S819.

[22] Asahi, Y.; Suzuki, T.; Sawada, A.; Kina, M.; Takada, J.; Gotoda, H.; Masuko, H. Pneumatosis cystoides intestinalis secondary to sunitinib treatment for gastrointestinal stromal tumor. Case Rep. Gastroenterol. 2018, 12, 432-438.

[23] Mendel, D.B.; Laird, A.D.; Xin, X.H.; Louie, S.G.; Christensen, J.G.; Li, G.M.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B.; Murray, L.J.; Carver, J.; Chan, E.; Moss, K.G.; Haznedar, J.O.; Sukbuntherng, J.; Blake, R.A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon, G.; Cherrington, J.M. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 2003, 9, 327-337.

[24] Abrams, T.J.; Lee, L.B.; Murray, L.J.; Pryer, N.K.; Cherrington, J.M. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol. Cancer Ther. 2003, 2, 471-478.

[25] Berberine. Altern. Med. Rev. 2000, 5, 175-177.

[26] Franceschin, M.; Rossetti, L.; D'Ambrosio, A.; Schirripa, S.; Bianco, A.; Ortaggi, G.; Savino, M.; Schultes, C.; Neidle, S. Natural and synthetic G-quadruplex interactive berberine derivatives. Bioorg. Med. Chem. Lett. 2006, 16, 1707-1711.

[27] Bessi, I.; Bazzicalupi, C.; Richter, C.; Jonker, H.R.; Saxena, K.; Sissi, C.; Chioccioli, M.; Bianco, S.; Bilia, A.R.; Schwalbe, H.; Gratteri, P. Spectroscopic, molecular modeling, and NMR-spectroscopic investigation of the binding mode of the natural alkaloids berberine and sanguinarine to human telomeric G-quadruplex DNA. ACS Chem. Biol. 2012, 7, 1109-1119.

[28] Fukuda, K.; Hibiya, Y.; Mutoh, M.; Koshiji, M.; Akao, S.; Fujiwara, H. Inhibition of activator protein 1 activity by berberine in human hepatoma cells. Planta Med. 1999, 65, 381-383.

[29] Sun, Y.Y.; Xun, K.L.; Wang, Y.T.; Chen, X.P. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs. 2009, 20, 757-769.

[30] Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 1984, 22, 27-55.