Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis synergistic upregulation of ALAS1 expression

Artemisinin and its derivatives (ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors (HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in non-erythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate (ARS) might have synergistic antitumor activity through modulating heme synthesis. studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase (ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.

Current developments in pharmacological therapeutics for chronic constipation

Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field.

Synthesis and biological activity of heterocycle-fused derivatives of pentacylic triterpenes as glycogen phosphorylase inhibitors / 中国药科大学学报

Aim: To search for novel modulators of glycogen metabolism through structural modifications of natural pentacyclic triterpenes. Methods: A series of N-heterocyclic derivatives were synthesized by fusing indole, qui-noxaline and pyrazine rings with A-ring of oleanolic and ursolic acids. The compounds were biologically evaluated for their inhibitory activity against rabbit muscle glycogen phosphorylase. Results and Conclusion: Twelve heter-ocyclic triterpene derivatives were synthesized and their structures were confirmed by IR, ~1H NMR, ~(13)C NMR and MS. Except for compound 12, all of the compounds exhibited glycogen phosphorylase inhibitory activity with IC_(50) values in the range of 14-252 μmol/L Among this series of compounds, compound 15 showed the best potency with IC_(50), of 14 μmol/L