Adenosine Analogues as Opposite Modulators of the Cisplatin Resistance of Ovarian Cancer Cells

Author(s): Katarzyna Bednarska-Szczepaniak*, Damian Krzyżanowski, Magdalena Klink*, Marek Nowak.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here, we determined the effect of adenosine analogues on the response of cisplatinsensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment.

Methods: The effects of PSB 36, DPCPX, SCH58261, ZM 241385, PSB603 and PSB 36 on cisplatin cytotoxicity were determined against A2780 and A2780cis cell lines. Quantification of the synergism/ antagonism of the compounds cytotoxicity was performed and their effects on the cell cycle, apoptosis/necrosis events and cisplatin incorporation in cancer cells were determined.

Results: PSB 36, an A1 receptor antagonist, sensitized cisplatin-resistant ovarian cancer cells to cisplatin from low to high micromolar concentrations. In contrast to PSB 36, the A2AR antagonist ZM 241385 had the opposite effect and reduced the influence of cisplatin on cancer cells, increasing their resistance to cisplatin cytotoxicity, decreasing cisplatin uptake, inhibiting cisplatin-induced cell cycle arrest, and partly restoring mitochondrial and plasma membrane potentials that were disturbed by cisplatin.

Conclusion: Adenosine analogues can modulate considerable sensitivity to cisplatin of ovarian cancer cells resistant to cisplatin. The possible direct beneficial or adverse effects of adenosine analogues on cancer cell biology should be considered in the context of supportive chemotherapy for ovarian cancer.

Keywords: Adenosine analogues, cisplatin resistance, ovarian cancer, antagonism, synergism, combination index.

Adaniel, C.; Kirchhoff, T. Introduction to epidemiology of breast and ovarian cancers. Ann. Oncol., 2013, 24(Suppl. 8), 61-62.
Li, K.; Hüsing, A.; Fortner, R.T.; Tjønneland, A.; Hansen, L.; Dossus, L.; Chang-Claude, J.; Bergmann, M.; Steffen, A.; Bamia, C.; Trichopoulos, D.; Trichopoulou, A.; Palli, D.; Mattiello, A.; Agnoli, C.; Tumino, R.; Onland-Moret, N.C.; Peeters, P.H.; Bueno-de-Mesquita, H.B.; Gram, I.T.; Weiderpass, E.; Snchez-Cantalejo, E.S.; Chirlaque, M-D.; Duell, E.J.; Ardanaz, E.; Idahl, A.; Lundin, E.; Khaw, K.; Travis, R.C.; Merritt, M.A.; Gunter, M.J.; Riboli, E.; Ferrari, P.; Terry, K.; Cramer, D.; Kaaks, R. An epidemiologic risk prediction model for ovarian cancer in Europe: The EPIC study. Br. J. Cancer, 2015, 112(7), 1257-1265.
Baldwin, L.A.; Huang, B.; Miller, R.W.; Tucker, T.; Goodrich, S.T.; Podzielinski, I.; DeSimone, C.P.; Ueland, F.R.; Nagell, J.R.; van Seamon, L.G. Ten-year relative survival for epithelial ovarian cancer. Obstet. Gynecol., 2012, 120(3), 612-618.
Jayson, G.C.; Kohn, E.C.; Kitchener, H.C.; Ledermann, J.A. Ovarian cancer. Lancet, 2014, 384(9951), 1376-1388.
Agarwal, R.; Kaye, S.B. Ovarian cancer: Strategies for overcoming resistance to chemotherapy. Nat. Rev. Cancer, 2003, 3(7), 502-516.
Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene, 2012, 31(15), 1869-1883.
Herzog, T.J. The current treatment of recurrent ovarian cancer. Curr. Oncol. Rep., 2006, 8(6), 448-454.
Chester, C.; Dorigo, O.; Berek, J.S.; Kohrt, H. Immunotherapeutic approaches to ovarian cancer treatment. J. Immunother. Cancer, 2015, 3(1), 7.
Beatty, G.L.; Gladney, W.L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res., 2014, 21(4), 687-692.
Kazemi, M.H.; Mohseni, S.R.; Hojjat-Farsangi, M.; Anvari, E.; Ghalamfarsa, G.; Mohammadi, H.; Jadidi-Niaragh, F. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J. Cell. Physiol., 2017, 233(3), 2032-2057.
Gessi, S.; Merighi, S.; Sacchetto, V.; Simioni, C.; Borea, P.A. Adenosine receptors and cancer. Biochim. Biophys. Acta BBABiomembr., 2011, 1808(5), 1400-1412.
Klink, M. Interaction of Immune and Cancer Cells; Springer Vienna, 2013.
Blay, J.; White, T.D.; Hoskin, D.W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res., 1997, 57(13), 2602-2605.
Virgilio, F.D.; Falzoni, S.; Giuliani, A.L.; Adinolfi, E. P2 receptors in cancer progression and metastatic spreading. Curr. Opin. Pharmacol., 2016, 29, 17-25.
Virgilio, F.D.; Adinolfi, E. Extracellular purines, purinergic receptors and tumor growth. Oncogene, 2016, 36(3), 293-303.
Muller-Haegele, S.; Muller, L.; Whiteside, T.L. Immunoregulatory activity of adenosine and its role in human cancer progression. Expert Rev. Clin. Immunol., 2014, 10(7), 897-914.
Sousa, J.B.; Fresco, P.; Diniz, C.; Goncalves, J. Adenosine receptor ligands on cancer therapy: A review of patent literature. Rec. Pat. Anticancer Drug Discov., 2018, 13(1), 40-69.
Young, A.; Ngiow, S.F.; Barkauskas, D.S.; Sult, E.; Hay, C.; Blake, S.J.; Huang, Q.; Liu, J.; Takeda, K.; Teng, M.W.L.; Sachsenmeier, K.; Smyth, M. Co-inhibition of cd73 and a2ar adenosine signaling improves anti-tumor immune responses. Cancer Cell, 2016, 30(3), 391-403.
Preti, D.; Baraldi, P.G.; Moorman, A.R.; Borea, P.A.; Varani, K. History and perspectives of a2aadenosine receptor antagonists as potential therapeutic agents. Med. Res. Rev., 2015, 35(4), 790-848.
Gessi, S.; Bencivenni, S.; Battistello, E.; Vincenzi, F.; Colotta, V.; Catarzi, D.; Varano, F.; Merighi, S.; Borea, P.A.; Varani, K. Inhibition of a2a adenosine receptor signaling in cancer cells proliferation by the novel antagonist TP455. Front. Pharmacol., 2017, 8, 888.
Mediavilla-Varela, M.; Luddy, K.; Noyes, D.; Khalil, F.K.; Neuger, A.M.; Soliman, H.; Antonia, S.J. Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol. Ther., 2013, 14(9), 860-868.
Chen, J.F.; Eltzschig, H.K.; Fredholm, B.B. Adenosine receptors as drug targets--what are the challenges? Nat. Rev. Drug Discov., 2013, 12(4), 265-286.
Mirza, A.; Basso, A.; Black, S.; Malkowski, M.; Kwee, L.; Patcher, J.A.; Lachowicz, J.E.; Wang, Y.; Liu, S. RNA interference targeting of a1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Cancer Biol. Ther., 2005, 4(12), 1355-1360.
Zhou, Y.; Tong, L.; Chu, X.; Deng, F.; Tang, J.; Tang, Y.; Dai, Y. The adenosine a1 receptor antagonist dpcpx inhibits tumor progression via the erk/jnk pathway in renal cell carcinoma. Cell. Physiol. Biochem., 2017, 43(2), 733-742.
Jin, D.; Fan, J.; Wang, L.; Thompson, L.F.; Liu, A.; Daniel, B.J.; Shin, T.; Curiel, T.J.; Zhang, B. CD73 on tumor cells impairs antitumor t-cell responses: A novel mechanism of tumor-induced immune suppression. Cancer Res., 2010, 70(6), 2245-2255.
Corbelini, P.F.; Figueiró, F. das Neves, G.M.; Andrade, S.; Kawano, D.F.; Oliveira Battastini, A.M.; Eifler-Lima, V.L. Insights into Ecto-5′-nucleotidase as a new target for cancer therapy: A medicinal chemistry study. Curr. Med. Chem., 2015, 22(15), 1776-1792.
Barcz, E.; Sommer, E.; Janik, P.; Marianowski, L.; Skopinska-Rózewska, E. Adenosine receptor antagonism causes inhibition of angiogenic activity of human ovarian cancer cells. Oncol. Rep., 2000, 7(6), 1285-1291.
Repetto, G.; Peso, A.; del Zurita, J.L. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat. Protoc., 2008, 3(7), 1125-1131.
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.
Klapperstück, T.; Glanz, D.; Klapperstück, M.; Wohlrab, J. Methodological aspects of measuring absolute values of membrane potential in human cells by flow cytometry. Cytometry A, 2009, 75A(7), 593-608.
Perry, S.W.; Norman, J.P.; Barbieri, J.; Brown, E.B.; Gelbard, H.A. Mitochondrial membrane potential probes and the proton gradient: A practical usage guide. Biotechniques, 2011, 50(2), 98-115.
Leone, R.D.; Emens, L.A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer, 2018, 6(1), 57.
Soleimani, A.; Bahreyni, A.; Roshan, M.K.; Soltani, A.; Ryzhikov, M.; Shafiee, M.; Soukhtanloo, M.; Jaafari, M.R.; Mashkani, B.; Hassanian, S.M. Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment, current status, and perspectives. J. Cell. Physiol., 2019, 234(3), 2329-2336.
Schiedel, A.C.; Lacher, S.K.; Linnemann, C.; Knolle, P.A.; Müller, C.E. Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms. Purinergic Signal., 2013, 9(3), 351-365.
Sun, W.; Moore, J.N.; Hurley, D.J.; Vandenplas, M.L.; Murray, T.F. Effects of stimulation of adenosine A2A receptors on lipopolysaccharide-induced production of reactive oxygen species by equine neutrophils. Am. J. Vet. Res., 2007, 68(6), 649-656.
Sun, W-C.; Moore, J.N.; Hurley, D.J.; Vandenplas, M.L.; Linden, J.; Cao, Z.; Murray, T.F. Adenosine A2A receptor agonists inhibit lipopolysaccharide-induced production of tumor necrosis factor-alpha by equine monocytes. Vet. Immunol. Immunopathol., 2008, 121(1-2), 91-100.
Kilian, J.G.; Nakhla, S.; Sieveking, D.P.; Celermajer, D.S. Adenosine prevents neutrophil adhesion to human endothelial cells after hypoxia/reoxygenation. Int. J. Cardiol., 2005, 105(3), 322-326.
Mueller, S.; Schittenhelm, M.; Honecker, F.; Malenke, E.; Lauber, K.; Wesselborg, S.; Hartmann, J.T.; Bokemeyer, C.; Mayer, F. Cell-cycle progression and response of germ cell tumors to cisplatin in vitro. Int. J. Oncol., 2006, 29(2), 471-479.
Daly, J.W. Caffeine analogs: Biomedical impact. Cell. Mol. Life Sci., 2007, 64(16), 2153-2169.
Chen, Y.; Hao, L-J.; Hung, C.; Chen, J.; Leu, S.; Huang, B. Apoptotic effect of cisplatin and cordycepin on oc3 human oral cancer cells. Chin. J. Integr. Med., 2013, 20(8), 624-632.
Gill, A.; Wortham, K.; Costa, D.; Davis, W.; Ticho, B.; Whalley, E. Protective effect of tonapofylline(BG9928), an adenosine A1 receptor antagonist, against cisplatin-induced acute kidney injury in rats. Am. J. Nephrol., 2009, 30(6), 521-526.
Tortora, G.; di Isernia, G.; Sandomenico, C.; Bianco, R.; Pomatico, G.; Pepe, S.; Bianco, A.R.; Ciardiello, F. Synergistic inhibition of growth and induction of apoptosis by 8-chloro-CAMP and paclitaxel or cisplatin in human cancer cells. Cancer Res., 1997, 57(22), 5107-5111.
Salamone, J.D. Preladenant, a novel adenosine A(2A) receptor antagonist for the potential treatment of parkinsonism and other disorders. Drugs Investig. Drugs J., 2010, 13(10), 723-731.
Hirama, M.; Isonishi, S.; Yasuda, M.; Ishikawa, H. Characterization of mitochondria in cisplatin-resistant human ovarian carcinoma cells. Oncol. Rep., 2006, 16(5), 997-1002.
Pathak, R.K.; Wen, R.; Kolishetti, N.; Dhar, S. A prodrug of two approved drugs, cisplatin and chlorambucil, for chemo war against cancer. Mol. Cancer Ther., 2017, 16(4), 625-636.
Knight, R.J.; Collis, M.G.; Yates, M.S.; Bowmer, C.J. Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine. Br. J. Pharmacol., 1991, 104(4), 1062-1068.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [473 - 486]
Pages: 14
DOI: 10.2174/1871520619666190118113201
Price: $58

Article Metrics

PDF: 27