Mechanisms and research progress of targeted therapies on regulation of autophagy by natural compounds from traditional Chinese medicine / 药学学报

Autophagy is an important physiological process that can degrade cell components and maintain cell homeostasis, divided into three types including macroautophagy, microautophagy and chaperon-mediated autophagy generally, and macroautophagy is the most common form. Autophagy can affect the progression of a variety of diseases, such as cancer, neurodegenerative diseases, heart-related diseases, and autoimmune diseases, etc. However, autophagy can promote or inhibit diseases in different circumstances because of the dual roles of autophagy. Therefore, targeted regulating autophagy may be a potential treatment plan for diseases in specific stages of disease development. Now, with the development of traditional Chinese medicine (TCM) resources and the deepening of researches on the modern utilization of TCM, many active compounds from TCM have been discovered that can target autophagy to exert pharmacological activity. Most of the natural compounds activate or inhibit autophagy by affecting the classical PI3K/AKT/mTOR autophagy pathway. In addition, some compounds can also affect autophagy through MAPKs signaling pathways such as MEK/ERK, JNK and p38MAPK. These active compounds exert various biological activities by regulating autophagy, including anti-tumor, inhibiting neurodegenerative diseases, protecting cardiomyocytes, and relief of inflammatory response. In this review, we summarized the active compounds in TCM that affect autophagy by targeting different signaling pathways and their mechanisms of regulating autophagy, also introduced the effects of active compounds on diseases after affecting autophagy. Finally, this paper summarized and prospected the development of targeted autophagy for the treatment of diseases by TCM compounds, hoping to provide clues for subsequent exploration and research.

Discovery of a small-molecule inhibitor of carbamoyl phosphate synthase 1 and its anti-colorectal cancer mechanism / 药学学报

The carbamoyl phosphate synthase 1 (CPS1) enzyme is involved in the first phase of the urea cycle, providing a prerequisite molecule for pyrimidine synthesis, as well as promoting tumor cell proliferation and growth. Studies have found that CPS1 is highly expressed in a variety of tumors, including colorectal cancer, lung cancer, etc. and its overexpression is related to the poor prognosis of tumors. Thus, small molecules targeted to inhibit the function of CPS1 in tumors may provide therapeutic benefits for cancer patients who overexpress CPS1. In this study, the function of CPS1 was investigated in vitro, and we found that overexpression of CPS1 can enhance the migration ability of colorectal cancer cells HCT15. Here, based upon the existing crystal structure, combined with high-throughput virtual screening, we obtained 8 candidate small molecule compounds. In vitro activity evaluation, we found that compound 3 has good anti-HCT15, HCT116 cell proliferation activity (HCT15, IC50, 7.69 ± 1.10 μmol‧L-1, HCT116, IC50, 13.53 ± 0.46 μmol‧L-1). Subsequently, molecular docking and molecular dynamics (MD) simulation analysis showed that, compound 3 could target and inhibit the activity of CPS1. In vitro studies showed that compound 3 could inhibit the migration of HCT15 cells, as well as induced cell cycle arrest and apoptosis. Taken together, this study found that compound 3 is a potential small molecule inhibitor that targets CPS1, which provides the experimental basis and theoretical basis for the development of targeted intervention small molecule therapeutic drugs. Based upon the chemical structure of compound 3, we will shed new light on further optimizing its activity and therapeutic potential, which may provide a therapeutic benefit to the patients with CPS1-related tumors.

Discovery of a small-molecule activator of beclin-1 that induces autophagy-associated cell death and apoptosis in triple negative breast cancer / 药学学报

Autophagy is a lysosomal degradation pathway, and plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. Here, combined with allosteric site identification methods, high-throughput virtual screening, and in vitro activity evaluation, we found that compound 10 can activate autophagy and has good anti-MDA-MB-231 cell proliferation activity (the half maximal inhibitory concentration IC50 = 8.25 ± 1.53 μmol·L-1). Subsequently, molecular docking, molecular dynamics simulation, and immunoblotting assay demonstrate that compound 10 can target and activate beclin-1. In vitro studies have shown that compound 10 can induce autophagy-associated cell death in MDA-MB-231 cells. In addition, it was found that compound 10 can induce apoptosis in MDA-MB-231 cells. Taken together, we identified the candidate compound 10 as an effective and selective targeting beclin-1 to activate autophagy as a lead compound, which provide a reference for further development and optimization of small molecule drugs targeting beclin-1 to activate autophagy for clinical treatment.