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    • Octreotide acetate Imatinib is a well known anticancer drug

    2022-12-02

    Imatinib is a well-known anticancer drug used in Chronic Myeloid Leukemia (CML) against the altered expression/activity of tyrosine kinase resulting from the fusion of BCR-ABL in leukemic blasts. It has been demonstrated that Imatinib can induce autophagy in BCR-ABL expressing Octreotide acetate (K562 cell line and blast cells isolated from CML patients) where the oncogenic protein is sequestered in autophagosomes. This observation represents a further example of the tumour suppressive role of autophagy in leukemia [48]. All Trans Retinoic Acid (ATRA) in combination with arsenic trioxide (ATO) represents a successful therapeutic treatment against Acute Promyelocitic Leukemia (APL). In this case, the combined treatment induced terminal differentiation in leukemic blasts exhibiting PML-RARα translocation and the autophagic degradation of this oncogenic protein contributed to explain the pharmacological efficacy of this targeted therapy [49]. These studies, however, show only one side of the story. If Imatinib is necessary to induce autophagosome degradation of BCR-ABL, following drug withdrawal, it also promotes leukemic cell recovery [50]. This can be explained by admitting that autophagy induced by Imatinib in residual blast cells, narrowed in bone marrow, resulted to be protective, supporting an unwanted drug resistance [51]. These studies suggest the need to identify a close space-temporal window where autophagy must be suppressed to avoid leukemia resistance [52]. Results from current human clinical trials involving autophagy modulators such as hydroxychloroquine in CML and MM (multiple myeloma) may contribute to bypass these obstacles and improve the anticancer therapy efficacy [52].
    Autophagy in tumour microenvironment and immune system If genetic studies are essential to understand in deep tumour biology, this approach only reveals some aspects of carcinogenesis, because cancer is not only a “genetic disease”. The real complexity of tumour biology has been excellently explained in pivotal scientific articles describing the “emerging” hallmarks of cancer, including the alterations of immune function and the role of tumour microenvironment. If cancer develops and spreads in the organism, this is due to a few initial genetic drivers mutations followed by other non-genotoxic events, such as tumour immune-surveillance failure [42], [53]. Considering cancer biology in this wider scenery, the opposite role of autophagy in sustaining or inhibiting cancer progression can be better understood. To this regard, an interesting study demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in tissue microenvironment, with the aim to obtain recycled molecules and a net energy transfer from tumour stroma to promote cancer growth. This new paradigm has been called “The Autophagic Tumour Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumour Growth” [54]. If this model is correct and confirmed by other studies, a way to avoid cancer resistance should foresee the induction of autophagy in epithelial cancer cells to prevent the use of recycled nutrient and the suppression of autophagy in surrounding stromal cells to obtain an effective starvation of neoplastic cells. The unsolved problem, however, is how to modulate autophagy with a correct and efficient combination of inducers and inhibitors in clinics. To complete the final picture resulting from “oncophagy”, it is worthwhile to remember that anticancer drugs are more efficacious if they induce “immunogenic cell death”, in other words stimulating an antineoplastic immune response. Michaud et al. demonstrated that autophagy is often dysfunctional in cancer cells, is not essential to induce cell death by chemotherapeutic drugs, but is required to attract immune cells (dendritic cells and T-lymphocytes) in tumour microenvironment [55]. The authors showed that ATP extracellular concentration is essential to induce immunogenic anticancer response because suppression of autophagy inhibited ATP efflux from dying tumour cells. On the opposite, increasing extracellular ATP by inhibition of degrading enzymes recruits immune cells and improve the efficacy of antineoplastic drugs in cancer where autophagy is disabled [55]. The final message is that “autophagy is essential for the immunogenic release of ATP from dying cells and to improve the efficacy of antineoplastic chemotherapies when autophagy is disabled” [55], [56].