Due to its pathophysiologic significance, the apoptosis/autophagic machinery is a promising target for new chemotherapeutic agents. Using both in vitro and in vivo techniques we showed that climacostol, a small organic product of the ciliate Climacostomum virens, has potent cytotoxic/pro-apoptotic effects, positively targeting the tumour suppressor p53. It exerts a sustained accumulation of autophagosomes in cells that are committed to die by apoptosis. Climacostol affects autophagosome turnover via p53-AMPK axis, although the mTOR pathway also plays a role. The up- regulation of p53 in the nuclei couples to p53 stability (phosphorylation at Ser15 site). Of interest, climacostol effects on autophagy and apoptosis are two separate events acting on life/death decisions of the cell. Since the p53 system is at the molecular crossroad regulating the autophagy impairment of climacostol and its role in apoptosis, it is important to explore the dual targeting of autophagy and apoptosis (via p53) for the selective killing of tumours. Thus, we synthesised three novel analogues of climacostol finding that the introduction of a methyl or a hydroxyl moiety to the aromatic ring effectively modulates its potency and mechanism of action. Also, we noticed that the methoxymethyl ether protecting group allowed us, thanks its easy removal in a weakly acidic environment, to optimise the synthesis of climacostol. The protected molecule (MOMO) was then analysed for its biological behaviour, since the pH control of drug responses is of great interest in the biomedical field. Here we provide a proof-of-concept study on the acidic pH-activation of MOMO to identify a new prodrug strategy for the generation of pH-sensitive small molecules as pharmacologically active cytotoxic compounds.

p53 system at the molecular crossroad regulating apoptosis/autophagy balance: natural bioactive compounds as small molecule killing tumours and dual targeting prodrug strategy

F Buonanno;C Ortenzi;
2019-01-01

Abstract

Due to its pathophysiologic significance, the apoptosis/autophagic machinery is a promising target for new chemotherapeutic agents. Using both in vitro and in vivo techniques we showed that climacostol, a small organic product of the ciliate Climacostomum virens, has potent cytotoxic/pro-apoptotic effects, positively targeting the tumour suppressor p53. It exerts a sustained accumulation of autophagosomes in cells that are committed to die by apoptosis. Climacostol affects autophagosome turnover via p53-AMPK axis, although the mTOR pathway also plays a role. The up- regulation of p53 in the nuclei couples to p53 stability (phosphorylation at Ser15 site). Of interest, climacostol effects on autophagy and apoptosis are two separate events acting on life/death decisions of the cell. Since the p53 system is at the molecular crossroad regulating the autophagy impairment of climacostol and its role in apoptosis, it is important to explore the dual targeting of autophagy and apoptosis (via p53) for the selective killing of tumours. Thus, we synthesised three novel analogues of climacostol finding that the introduction of a methyl or a hydroxyl moiety to the aromatic ring effectively modulates its potency and mechanism of action. Also, we noticed that the methoxymethyl ether protecting group allowed us, thanks its easy removal in a weakly acidic environment, to optimise the synthesis of climacostol. The protected molecule (MOMO) was then analysed for its biological behaviour, since the pH control of drug responses is of great interest in the biomedical field. Here we provide a proof-of-concept study on the acidic pH-activation of MOMO to identify a new prodrug strategy for the generation of pH-sensitive small molecules as pharmacologically active cytotoxic compounds.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11393/255298
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