Adenosine enhances cisplatin sensitivity in human ovarian cancer cells

Abstract

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-IC 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.

Long Intergenic Noncoding RNA OIN1 Promotes Ovarian Cancer Growth by Modulating Apoptosis-Related Gene Expression

“…Conversely, ADORA1 was reported to promote the growth and survival of 786-O and ACHN kidney cancer cells, or MDA-MB-468 breast cancer cells [ 34 , 35 ]. Notably, treatment with the ADORA1 antagonist SLV320 partially rescued the adenosine-mediated decrease in A2780 cell survival, suggesting that ADORA1 may play a tumor-suppressive role in ovarian cancer [ 36 ].…”

Artemisinin induced reversal of EMT affects the molecular biological activity of ovarian cancer SKOV3 cell lines

“…Ovarian cancer the highest mortality rates amongst gynecological malignancies. Metastasis, drug resistance, and recurrence are important factors leading to patient mortality (1). At present, the clinical treatment of ovarian cancer is a multidisciplinary comprehensive process, and cytoreductive surgery combined with platinum-based chemotherapy is the current standard treatment (13–16).…”

“…Ovarian cancer has the highest mortality of reproductive system tumors; most patients have already progressed to a late stage when diagnosed due to the high invasiveness and recurrence of ovarian tumors (1–4). Epithelial-mesenchymal transition (EMT) is the biological process during which epithelial cells acquire abnormal motor forces due to specific environmental changes or pathological factors, and transform from an epithelial phenotype to an interstitial phenotype (5,6).…”

Ghrelin enhances cisplatin sensitivity in HO-8910 PM human ovarian cancer cells

“…Development of resistance to platinum-based chemotherapy is one of the crucial problems in ovarian cancer treatment. Patients experiencing relapses later than 6 months following a response to platinum-based therapy are characterized as having platinum-sensitive disease, whereas patients who experience recurrences within 6 months following an initial response to platinum-based therapy are defined as having platinum-resistant ovarian cancers [5]. Therefore, reducing platinum-resistant is an important way to suppress relapses and the mortality rate.…”