Abstract
BackgroundIron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells.MethodsWe used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways.ResultsIn our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells.Conclusions: DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.
Highlights
Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient
We have investigated the ability of DFX ability to suppress tumour proliferation, and found that it suppresses proliferation in a concentration-dependent manner [10], it improves sensitivity to GEM [11], and that the combination of DFX and sorafenib is better than DFX alone at suppressing liver cancer [12]; we have examined other secondary effects of iron chelators
Because the results of a micro-array analysis showed a decline in expression of Rac1 and Cdc42, similar experiments were performed with the Rac1 inhibitor NSC 23766 and the Cdc42 inhibitor ML141
Summary
Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. FOLFIRINOX therapy [4], a combination of fluorouracil, irinotecan, oxaliplatin, and leucovorin [4], and GEM plus nab-paclitaxel [5] has been reported to be useful. While these kinds of combination chemotherapies have comparatively higher therapeutic effects than GEM monotherapy, they have higher incidence rates of side effects like cytopenia. More than half of all pancreatic cancer patients are diagnosed at age 65 or older [6] It is vital, especially for elderly pancreatic cancer patients, that new chemotherapies with low side-effect incidence rates be studied
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