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  • Several approved and or experimental drugs together

    2024-07-10

    Several approved and/or experimental drugs, together with natural compounds, have been reported to induce autophagy in different cancer types [70], [71], [72] (Table 1). In the next paragraphs, we will review more in detail a group of these agents selected in relation to their promising future outcomes. However, it must be underlined that in the large majority of cases, data are referring to pre-clinical studies and the 1 646 mg investigated, especially those present in foods and herbs, are known for their pleiotropic modes of actions, making difficult to identify a specific molecular mechanism. In the examples of drugs already approved by international drug agencies, many of them are on the market as remedies against diseases different from cancer (refer to Table 4 in [70] and Table 1 in 1 646 mg [71] and references therein). This is the case of few FDA-approved drugs employed in the treatment of different clinical conditions such as neurodegenerative disorders, aging, metabolic, infectious diseases and also able to induce autophagy. Two of them, metformin and rapamycin, will be further reviewed here for their potential role in cancer treatment (Table 1, Fig. 2).
    Conclusions We learned from the discussion reported above that the main obstacle in developing autophagy inducers in clinics is represented by the dual and opposite functions of autophagy in cancer cells. In specific circumstances, depending on the genetic background, stage of the tumour, etc. autophagy can be “protective”, reducing the effects of different cellular stresses and promoting an unwanted survival of malignant cells, or, on the opposite, can potentiate different forms of cell death. For almost all the examples discussed above and referring to synthetic or natural compounds, we reported cases where the same molecule activated the autophagic flux, but the result in terms of cancer cell survival resulted controversial. Perhaps, one of the key questions regards the appropriateness of the pre-clinical models employed. Especially when we are dealing with pleiotropic compounds, both drugs or natural agents, their low specificity can generate artifacts if the treatment is performed exclusively on cell lines. This criticism is not novel and is shared by the large class of phytochemicals. As an example, we recently reviewed the controversial effects of polyphenols as antioxidants in cancer therapy and prevention ending up with the conclusion that the inappropriate use of cellular and animal model generated a significant part of the confusion and contradictory results present in the literature [129]. Of course, we can suggest a more rational selection of adequate cell lines, where the main autophagic pathways have been identified and characterized, before starting the treatment with potential autophagy inducers in mono-treatment or, as often reported, in combination with other drugs. However, for autophagy, this may not be enough. As briefly reported at the beginning of this article, the field “exploded” in the last few years. The complexity of this process multiplied the number of specific assays and, consequently, the reagents and methods available to better assess the autophagy pathways under investigation. Fortunately, periodically, guidelines are published to help the researchers to better examine macroautophagy and related processes, as well as reviewers to critically evaluate autophagy related manuscripts [4], [130], [131]. As an example, until few years ago, a simple immunoblot showing the change in the expression of LC3 or the ratio LC3-II/LC3-I was considered sufficient to define the presence of an ongoing process of autophagy. Nowadays, it is mandatory to identify the autophagic pathway investigating by gene knockout or RNA interference, in addition to assess the expression of multiple autophagy-related proteins. Moreover, the functional pleiotropy of Atg proteins, which are involved in other cellular pathways, implies that not all of them can be employed as unique and specific marker for a defined autophagic process [130]. As a corollary, the conclusions deriving from articles published before the last 5–7 years and dealing with autophagy regulation should be carefully taken into consideration if the currently accepted methodological criteria have not been applied.