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  • If the lack of specificity and

    2024-04-01

    If the lack of specificity and the high pleiotropy may represent a problem in view of the potential chemotherapeutic features of autophagy-inducing agents, it GPCR Compound Library sale may switch into an advantage in the case of chemopreventive strategies. In fact, as non-pharmacologic interventions such as limited caloric intake and moderate exercise can induce autophagy and ameliorate health, several approved drugs and natural agents can mimic this effect. This role is emerging for degenerative and infectious diseases and can be also extended to primary and secondary cancer chemoprevention where low dosage and prolonged drug administration is required. In this case, the tolerability of the non-autophagic adverse effects of autophagy-inducing agents can be mild and acceptable with the result that, at the low doses applied, only the desirable autophagy outcomes prevail. To this regard, the observation that the toxicity of rapalogs can be very low and their main effects result in the capacity to slow-down cancer cell growth has been recently confirmed by a recent work from our laboratory where a carotenoid extract triggered nonprotective autophagy by inducing a delay in cell growth [132]. However, this possible interpretation cannot lower the attention on searching for new autophagy inducers characterized by high specificity and limited side effects. A great attention in designing new autophagy inducers in cancer treatment must be given to the interplay between autophagy and other processes regulating cell death and cell survival, such as apoptosis. As an example, new BH3 mimetics may interfere with the binding between Beclin-1 and Bcl-2 members with anti-apoptotic functions, but also influence the binding between the pro-apoptotic and the anti-apoptotic Bcl-2 family members resulting in reduced specificity towards autophagy regulation and potentially increased side effects. It would be desirable that, based on the structural determinants involved in the Beclin-1 binding to BH3 domain, only BH3 mimetics highly specific for autophagy induction will be designed. Other autophagic molecular targets may result more promising being, theoretically, less influenced by not specific interactions. To this regard, post-translation modifications (phosphorylations / dephosphorylation, acetylations / deacetylation, ubiquitynations / deubiquitynations) on Ulk1 represents promising targets for new autophagy inducers [133]. As an example, the activation of TIP60, which acetylates and activates Ulk1 [134] and/or the Ulk1 ubiquitylation and activation by AMBRA1/E3-ligase TRAF6 complex [135] may have the advantage to highly specifically enhance autophagy, without influencing other regulatory pathways. The novel identified compounds must show their effectiveness at physiological and pharmacological concentrations and respond to the methodological priorities discussed above, such as: a) the putative new inducers should be inactivated when autophagy genes are shut-off; b) their specific and direct target(s) must be identified and confirmed showing that their over-expression or knockout enhance or abolish, respectively, the pro-autophagy effects. Partial progresses have been obtained by large screenings based on the detection of GFP-LC3 puncta and/or LC3 expression as markers of autophagosomes presence [136], [137], [138]. Strategies can also take advantage of bioinformatics approach aimed to characterize protein interactomics and phosphoproteomics in autophagy pathways, or, alternatively, as discussed above, scientists can develop autophagy inducers able to trigger key components in the regulatory autophagy pathway, which are unique and absolutely required to activate downstream events. However, without a robust validation of the biological activity of these candidates in adequate pre-clinical models followed by clinical trials, their validity remains elusive. To this regard, it is worthwhile to note that searching for ongoing clinical studies in cancer prevention or therapy based on the treatment with the potential autophagy inducers reviewed in the present work, we did not retrieve any significant results.