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We have previously demonstrated that the thiazole derivative 3-methylcyclopentylidene-[4-(40-chlorophenyl)thiazol-2-yl]\udhydrazone (CPTH6) induces apoptosis and cell cycle arrest in human leukemia cells. The aim of this study was to evaluate\udwhether CPTH6 is able to affect autophagy. By using several human tumor cell lines with different origins we demonstrated that\udCPTH6 treatment induced, in a dose-dependent manner, a significant increase in autophagic features, as imaged by electron\udmicroscopy, immunoblotting analysis of membrane-bound form of microtubule-associated protein 1 light chain 3 (LC3B-II) levels\udand by appearance of typical LC3B-II-associated autophagosomal puncta. To gain insights into the molecular mechanisms of\udelevated markers of autophagy induced by CPTH6 treatment, we silenced the expression of several proteins acting at different\udsteps of autophagy. We found that the effect of CPTH6 on autophagy developed through a noncanonical mechanism that did not\udrequire beclin-1-dependent nucleation, but involved Atg-7-mediated elongation of autophagosomal membranes. Strikingly, a\udcombined treatment of CPTH6 with late-stage autophagy inhibitors, such as chloroquine and bafilomycin A1, demonstrates that\udunder basal condition CPTH6 reduces autophagosome turnover through an impairment of their degradation pathway, rather than\udenhancing autophagosome formation, as confirmed by immunofluorescence experiments. According to these results, CPTH6-\udinduced enhancement of autophagy substrate p62 and NBR1 protein levels confirms a blockage of autophagic cargo\uddegradation. In addition, CPTH6 inhibited autophagosome maturation and compounds having high structural similarities with\udCPTH6 produced similar effects on the autophagic pathway. Finally, the evidence that CPTH6 treatment decreased a-tubulin\udacetylation and failed to increase autophagic markers in cells in which acetyltransferase ATAT1 expression was silenced\udindicates a possible role of a-tubulin acetylation in CPTH6-induced alteration in autophagy. Overall, CPTH6 could be a valuable\udagent for the treatment of cancer and should be further studied as a possible antineoplastic agent

The thiazole derivative CPTH6 impairs autophagy