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  • Another TKI used in cancer therapy


    Another TKI used in cancer therapy is the Abl inhibitor imatinib mesilate which has also a beneficial effect on glucose homeostasis in diabetic humans [39], [40], [41]. Imatinib has a clear impact on NFκB activation and anti-apoptotic preconditioning of β-cells [39], attenuating islet inflammation [40] and improving β-cell survival [41]. No direct action of sunitinib on NFκB in β-cells was reported so far. It has been shown, however, that sunitinib modulates neuronal survival in vitro via NFκB signalling [42] and the TKI might exert similar effects in β-cells. Furthermore, c-Kit, another sunitinib target kinase, seems to play a role in β-cell survival, since a mouse model with a c-Kit mutation has reduced β-cell mass [43]. Beyond possible anti-apoptotic effects, sunitinib may also interfere with the cellular calcium homeostasis. In human cardiomyocytes, sunitinib impaired cytosolic Ca handling by decreasing Ca transients [44]. Such a negative effect on cytosolic Ca handling in β-cells is unlikely, since it would not increase but reduce GIIS. In addition, sunitinib treatment has been reported to increase activity of the calcium/calmodulin-dependent protein kinase II in cardiomyocytes [45]. Putative effects of sunitinib on calcium homeostasis and calcium/calmodulin-dependent protein kinase II in β-cells need further experimental evidence.
    Conflicts of interest
    Acknowledgements The authors thank Dorothea Neuscheler (University Hospital Tübingen, Tübingen Germany), Sieglinde Haug (University Hospital Tübingen, Tübingen Germany) and Elisabeth Metzinger (University Hospital Tübingen, Tübingen Germany) for skilled technical assistance. The study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD e.V.).
    Introduction Ovarian cancer accounts for 4% of all female cancers and over 150,000 women die each year around the world as a result of this disease [1]. Ovarian cancer Sodium ascorbate seem to have a predilection for omental metastasis, with over 50% of the patients presenting with omental disease at the time of diagnosis [2], [3]. In addition to malignancies of the ovary, the omentum is also a metastatic niche for breast [4] and gastroenterological cancers including gastric [5] and colonic [6]. This homing of ovarian cancer cells has been attributed to the adipocytes and the immune rich ‘milky spots’ that enrich the omentum [7], [8]. The interaction between omental adipocytes and ovarian cancer growth has recently become an area of increased interest. The tumor promoting effects of adipocytes have been partly attributed to the release of free fatty acids (FFAs) as they undergo lipolysis. By co-culturing adipocytes loaded with fluorescently labeled lipids and SKOV3ip1 ovarian cancer cells, Nieman et al. showed direct transfer of fatty acids from adipocytes to ovarian cancer cells as opposed to de novo lipid synthesis [7]. In addition to serving as fuel to the growing cancer cells by providing free fatty acids, adipocytes are capable of endocrine and immunological functions and thus it is not surprising that more than one mechanism would be involved in promoting ovarian cancer growth. The adipokine leptin, interleukin (IL) 6, IL8, chemokine (C–C motif) ligand 2 (CCL2), and tissue inhibitor of metalloproteinases-1 secreted by adipocytes have all been shown to play a role in ovarian cancer pathogenesis [9], [10], [11]. Additionally, adipocytes have been implicated to play a role in chemoresistance and radioresistance [12]. In a previous study, we have shown that adipocyte-conditioned media significantly increased the proliferation, migration and invasion of ID8 mouse ovarian cancer cells. Such treatment was also associated with induction of various pro-tumorigenic genes and inhibition of apoptosis related genes in the ovarian cancer cells [9]. Exposure to adipocyte-conditioned media also changed the energy kinetics of the cancer cells by increasing glycolysis and oxidative phosphorylation [9].