The targeting of BCR-ABL, a hybrid oncogenic tyrosine (Y) kinase, does not eradicate chronic myeloid leukemia (CML)-initiating cells. Activation of ␤-catenin was linked to CML leukemogenesis and drug resistance through its BCR-ABLdependent Y phosphorylation and impaired binding to GSK3␤ (glycogen synthase kinase 3␤). Herein, we show that GSK3␤ is constitutively Y 216 phosphoactivated and predominantly relocated to the cytoplasm in primary CML stem/ progenitor cells compared with its balanced active/inactive levels and cytosolic/ nuclear distribution in normal cells. Under cytokine support, persistent GSK3␤ activity and its altered subcellular localization were correlated with BCR-ABL-dependent and -independent activation of MAPK and p60-SRC/GSK3␤ complex formation. Specifically, GSK3␤ activity and nuclear import were increased by imatinib mesylate (IM), a selective ABL inhibitor, but prevented by dasatinib that targets both BCR-ABL-and cytokine-dependent MAPK/p60-SRC activity. SB216763, a specific GSK3 inhibitor, promoted an almost complete suppression of primary CML stem/progenitor cells when combined with IM, but not dasatinib, while sparing bcr-abl-negative cells. Our data indicate that GSK3 inhibition acts to prime a pro-differentiative/apoptotic transcription program in the nucleus of IM-treated CML cells by affecting the ␤-catenin, cyclinD1, C-EBP␣, ATF5, mTOR, and p27 levels. In conclusion, our data gain new insight in CML biology, indicating that GSK3 inhibitors may be of therapeutic value in selectively targeting leukemia-initiating cells in combination with IM but not dasatinib.

The epithelial to mesenchymal transition (EMT) is a cellular program associated with the organ morphogenesis but also with the disease progression. EMT in the cancer field fuels neoplastic progression promoting the resistance to cell death, the resistance to chemotherapy and the acquisition of stem cell properties. Considering the crucial role of EMT in breast cancer metastasis, a better understanding of this process may provide new therapeutic options. Here, by using a proteomic approach we identified a set of proteins differentially expressed between an epithelial and a mesenchymal breast cancer cell line. The protein-protein network of these identified proteins was determined by an in silico analysis highlighting, in the EMT program, the role of proteins involved in cell adhesion, migration, and invasion, together with protein kinases involved in proliferation and survival, with many of these emerging as possible targets of novel biological agents. Finally, the pharmacological inhibition of some of these kinases was able to reverse the mesenchymal phenotype to an epithelial phenotype.

Curcumin is a natural hydrophobic polyphenol found in the powdered rhizomes of Curcuma longa. Due to its capacity to interfere with many signalling pathways, it has been shown that curcumin has potential beneficial pharmacological effects including antioxidant, anti-inflammatory, anticarcinogenic properties.However, the use of curcumin is fairly restricted because of its poor water solubility, low bioavailability, inadequate tissue absorption and degradation at alkaline pH. In the present contribution, we first verified the anti-proliferative effects of natural curcuminoids towards two different cell lines derived from an ovarian and a breast adenocarcinoma cancer. Later, curcuminoids were successfully encapsulated into reconstituted oil bodies. Once encapsulated into the triacylglycerol cores of the reconstituted oil bodies, curcumin, the most hydrophobic and active of the three curcuminoids, was better stabilized in comparison with albumin stabilization. Oil body encapsulated curcuminoids showed the same effects on cancer cell viability as the free drug, confirming the great potential of natural oil bodies as micro/nano-capsules in drug delivery applications.