Two Kinds Of Small Molecule Compounds Modulated Autophagy And Related Biological Function

Autophagy as an important biological process, has become a rapidly developing research field in the past two decades. And it has been listed on Science as one of the six popular events of the2005technology field, which indicated that autophagy had attaracted more and more serious concern. In fact, more and more new scientists have entered this field and the knowledge base and new technologies have been expanding. In eukaryotic cells, autophagy is a very conservative process which involves the rearrangement of subcellular membranes to sequester proteins of cytoplasm and intercellular organelles for delivery to lysosome where the sequestered material is degraded and recycled. Autophagy as a widespread biological process in eukaryotes, is very important for the metabolic needs of the cell and to maintain the balance of homeostasis. In addition to its basic role in the turnover of proteins and organelles, many studies have shed light on its multiple physiological and pathophysiological functions. To assist in the treatment of the disease by regulation of autophagy has become a new research direction. In this paper, we introduce two small molecule compounds which have the ability of regulating autophagy in tumor cells and also have potential biological functions.In the first part of the work, we reported that small molecule dye Hoechst33342can induce not only caspase-independent cell death in HeLa cells but also authentic autophagy by steady state methods and flux measurements. It is interesting that ROS was respectively involved in caspase-independent cell death and autophagy induced by Hoechst33342, and ROS inhibitor reduced both GFP-LC3puncta formation and the percentage of pyknotic cells. There is no clear conclusion on the relationship between autophagy and apoptosis, and often have to be analyzed according to the specific circumstances. In this paper, we also evaluated the relationship between autophagy and caspase-independent cell death induced by Hoechst33342. The results showed that cell death induced by Hoechst33342was enhanced under pharmacological and siRNA-mediated genetic inhibition of autophagy, which suggested that autophagy played a protective role against caspase-independent cell death in HeLa cells. This part of work demonstrated a previously-unknown autophagy-augmenting effect for Hoechst33342and further revealed a novel and interesting relationship between ROS, autophagy and caspase-independent cell death manifested by Hoechst33342.In the second part of the work, we studied on paeonol, a phenolic component from the root bark of Paeonia moutan, which is traditionally used as a Chinese herbal medicine. Paeonol has been identified to have various pharmacological and physiological effects, such as sedation, hypnosis, antipyresis, analgesia, antioxidation, anti-inflammation, anti-bacteria, immuno-regulation, and anti-tumor. Especially in the aspect of anti-tumor, many studies have shown that paeonol can promote apoptosis and inhibited the proliferation of different tumor cell lines. In our study, paeonol was proved to cause autophagosome accumulation in HeLa cells. Furthermore, paeonol had a synergistic effect when combined with Dox (doxorubicin) in vitro experiments. Paeonol sensitized doxorubicin-elicited HeLa cell death, which also appeared in the doxorubicin-resistant MCF-7cells (MCF-Dox). Finally, we demonstrated that the chemosensitization effect of paeonol was dependent on its ability to regulate autophagy, as inhibition of autophagy signifcantly reduced the chemosensitization effect of paeonol. Our results revealed novel biological functions of paeonol in autophagy and enhancing the chemotherapeutic effect of doxorubicin, which pointed to the potential use of paeonol in adjunct cancer therapy.