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  • From these and other studies it is clear that

    2020-09-16

    From these and other studies, it is clear that acriflavine is an interesting ID-8 with pleiotropic anticancer effects [21], [22], [43]. Its past systemic use in the clinical setting as an antibiotic without any major toxicity reported encourages further development of the drug for cancer treatment [44]. We hypothesize that ACF pushes the cancer cell to an epithelial state, blocking the development of drug resistance and prolonging the time frame over which a drug can have its effect on the tumor and so increasing its effectiveness. However, at present no preparation for clinical use is available and the interest of the industry in off-patent drugs is limited [45]. We believe studies like these should prompt non-profit institutions to take initiatives that allow repurposing acriflavine for animal and clinical testing in oncology.
    Acknowledgements We acknowledge our use of the gene set enrichment analysis, GSEA software, and Molecular Signature Database (MSigDB) (Subramanian, Tamayo, et al. (2005), PNAS 102, 15545-15550, http://www.broad.mit.edu/gsea/). We thank prof. Landowski for providing us with the gemcitabine resistant MiaPaCa-2 cell lines and prof. Stein Aerts and his colleagues for the discussion on the iRegulon results. CV holds a mandate as Senior Clinical Investigator of the Research Foundation - Flanders (Belgium) (FWO). This study was partly supported by a research grant from “Kom op tegen Kanker” Belgium and VUYLSTEKE-FLIPTS FONDS LEVERKANKER.
    Introduction PTEN is a powerful tumor suppressor gene that is frequently mutated in human cancer (Li et al., 1997, Steck et al., 1997, Teng et al., 1997). Germline mutations of PTEN are associated with tumor-susceptibility diseases, such as Cowden syndrome, which is characterized by multiple hamartomas (Liaw et al., 1997, Nelen et al., 1997). The role of PTEN as a potent tumor suppressor has been demonstrated in many animal models, where Pten deletion leads to development of various types of tumors that mimic the spectrum of human cancers associated with PTEN mutations (Di Cristofano et al., 1998, Podsypanina et al., 1999, Stambolic et al., 2000). Pten loss also results in neurological defects and metabolic disorders (Gasser, 2007, Stiles et al., 2004, Stiles et al., 2006), suggesting that PTEN function is not limited to tumor suppression. PTEN is essential for embryonic development as homozygous Pten deletion results in developmental defects and embryonic lethality (Di Cristofano et al., 1998, Podsypanina et al., 1999, Suzuki et al., 1998). These findings all demonstrate the importance of PTEN in a diversity of biological processes including embryonic development, tissue homeostasis, metabolism, and tumor suppression. PTEN resides at the 10q23 locus and encodes a 403 amino acid (aa) protein with an N-terminal phosphatase domain (Li et al., 1997, Steck et al., 1997). The primary substrate of PTEN phosphatase is phosphatidylinositol-3,4,5-triphosphate (PIP3), a critical messenger for activation of the phosphoinositide-3-kinase (PI3K)/AKT pathway (Maehama and Dixon, 1998). PTEN dephosphorylates PIP3 at the plasma membrane and negatively regulates PI3K/AKT-mediated cell survival and proliferation. In the nucleus, PTEN maintains chromosomal integrity by stabilizing centromeres (Shen et al., 2007) and regulates cellular senescence through APC-CDH1-mediated protein degradation (Song et al., 2011). These nuclear PTEN functions are phosphatase independent and unrelated to the PI3K/AKT pathway (Shen et al., 2007, Song et al., 2011). These findings indicate that PTEN functions to control diverse fundamental biological processes, which cannot be attributed merely to its phosphatase activity or to its regulation of the PI3K/AKT pathway. It is therefore likely that some severe observed consequences of PTEN dysfunction result from loss of PTEN functions that are as yet unidentified. Alternatively, unidentified forms of PTEN may exist that serve in roles previously assumed to be functions of canonical PTEN.