Adenosine enhances cisplatin sensitivity in human ovarian cancer cells
Ovarian cancer is the deadliest gynecologic cancer due to lack of early effective diagnosis and development of resistance to platinum-based chemotherapy. Several studies reported that adenosine concentrations are higher in tumor microenvironment than in non-tumor tissue. This finding inspired us to study the role of adenosine in ovarian cancer cells and to investigate if adenosine pathways offer new treatment options urgently needed to prevent or overcome chemoresistance. The ovarian cancer cell lines HEY, A2780, and its cisplatin-resistant subline A2780CisR were used in this study. Expression and functional activity of adenosine receptors were investigated by RT-PCR, Western blotting, and cAMP assay. A1 and A2B adenosine receptors were expressed and functionally active in all three cell lines. Adenosine showed moderate cytotoxicity (MTT-IC50 values were between 700 and 900 μM) and induced apoptosis in a concentration-dependent manner by increasing levels of sub-G1 and cleaved PARP. Apoptosis was diminished by QVD-OPh, confirming caspase-dependent induction of apoptosis. Forty-eight hours pre-incubation of adenosine prior to cisplatin significantly enhanced cisplatin-induced cytotoxicity in a synergistic manner and increased apoptosis. SLV320 or PSB603, selective A1 and A2B antagonists, was not able to inhibit adenosine-induced increase in cisplatin cytotoxicity or apoptosis whereas dipyridamole, a nucleoside transporter inhibitor, completely abrogated both effects. Mechanistically, adenosine increased pAMPK and reduced pS6K which was prevented by dipyridamole. In conclusion, application of adenosine prior to cisplatin could be a new therapeutic option to increase the potency of cisplatin in a synergistic manner and thus overcome platinum resistance in ovarian cancer.
KeywordsAdenosine Ovarian cancer Cisplatin Adenosine receptors Nucleoside transporter Dipyridamole
This study was supported by the Bundesministerium für Forschung (BMBF, Germany, Grant: BMBF-16GW0108). We acknowledge funding by the DFG for the Thermofisher Arrayscan XTI (Grant: INST 208/690-1 FUGG).
Compliance with ethical standards
Conflicts of interest
All the authors declare that they have no conflict of interest.
This article does not contain any studies with participants or animals performed by any of the authors.
- 1.Coward JI, Middleton K, Murphy F (2016) New perspectives on targeted therapy in ovarian cancer. Int J Womens Health 7:189–203Google Scholar
- 3.Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C (2013;24 Suppl 6) Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol:vi24–vi32Google Scholar
- 4.Foley OW, Rauh-Hain JA, Carmen MG (2013) Recurrent epithelial ovarian cancer: an update on treatment. Oncology (Williston Park) 27(4):288–294 298Google Scholar
- 13.US Food & Drug Administration (USFDA). Adenosine. https://www.accessdata.fda.gov. Accessed 27 July 2017
- 26.Stenzel K, Hamacher A, Hansen FK, Gertzen CGW, Senger J, Marquardt V, Marek L, Marek M, Romier C, Remke M, Jung M, Gohlke H, Kassack MU, Kurz T (2017) Alkoxyurean-based histone deacetylase inhibitors increase cisplatin potency in chemoresistant cancer cell lines. J Med Chem 60(13):5334–5348PubMedCrossRefGoogle Scholar
- 29.Kalk P, Eggert B, Relle K, Godes M, Heiden S, Sharkovska Y, Fischer Y, Ziegler D, Bielenberg GW, Hocher B (2007) The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br J Pharmacol 151(7):1025–1032PubMedPubMedCentralCrossRefGoogle Scholar
- 36.Mello Pde A, Coutinho-Silva R, Savio LEB (2017) Multifaceted effects of extracellular adenosine triphosphate and adenosine in the tumor–host interaction and therapeutic perspectives. Frontier Immunol 8 article 1526Google Scholar
- 41.Montalban Del Barrio I, Penski C, Schlahsa L, Stein RG, Diessner J, Wockel A et al (2016) Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages—a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape. J Immunother Cancer 4:49PubMedPubMedCentralCrossRefGoogle Scholar
- 44.Fernández ML, DiMattia GE, Dawson A, Bamford S, Anderson S, Hennessy BT, Anglesio MS, Shepherd TG, Salamanca C, Hoenisch J, Tinker A, Huntsman DG, Carey MS (2016) Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines. Am J Cancer Res 6(10):2235–2251PubMedPubMedCentralGoogle Scholar