Abstract
Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer.
Highlights
Ovarian cancer is the most lethal gynecologic cancer and the seventh-most common cancer in women worldwide [1]
To further confirm the induction of apoptosis by DFMO in human ovarian cancer cells, we performed an analysis of apoptosis activity and the apoptosis signaling pathway
The cells treated with DFMO were assessed using Annexin V or Caspase-3 assays, and the results showed that DFMO dramatically increased apoptosis and caspase-3 activity in a dose-dependent manner (Figure 1C,D)
Summary
Ovarian cancer is the most lethal gynecologic cancer and the seventh-most common cancer in women worldwide [1]. New treatments for ovarian cancer have been developed; these treatment strategies encounter a significant amount of resistance because of their heterogeneity in pathologic and genetic variants [2]. Studies on long-term maintenance therapy, or combinations of existing therapeutic approaches to overcome resistance and reduce mortality, are ongoing. Cancer metabolism is an important component of cancer cell survival and an emerging target of anti-cancer agents. Polyamines, including putrescine, spermidine, and spermine, are essential for the survival of cancer cells [3]. Inhibition of the polyamine pathway results in anti-tumor effects via apoptotic signaling pathways
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