Abstract
Resistance of cancer cells to chemotherapy is a significant problem in oncology, and the development of sensitising agents or small-molecules with new mechanisms of action to kill these cells is needed. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged organelles, and it also recycles nutrients to maintain energy levels for cell survival. In some apoptosis-resistant cancer cells, autophagy can also enhance the efficacy of anti-cancer drugs through autophagy-mediated mechanisms of cell death. Because the modulation of autophagic processes can be therapeutically useful to circumvent chemoresistance and enhance the effects of cancer treatment, the identification of novel autophagic enhancers for use in oncology is highly desirable. Many novel anti-cancer compounds have been isolated from natural products; therefore, we worked to discover natural, anti-cancer small-molecule enhancers of autophagy. Here, we have identified a group of natural alkaloid small-molecules that function as novel autophagic enhancers. These alkaloids, including liensinine, isoliensinine, dauricine and cepharanthine, stimulated AMPK-mTOR dependent induction of autophagy and autophagic cell death in a panel of apoptosis-resistant cells. Taken together, our work provides novel insights into the biological functions, mechanisms and potential therapeutic values of alkaloids for the induction of autophagy.
Highlights
Betty Yuen Kwan Law, Wai Kit Chan, Su Wei Xu, Jing Rong Wang, Li Ping Bai, Liang Liu & Vincent Kam Wai Wong
Using bioactivity-guided screening of selected compounds isolated from natural products, we have identified a group of alkaloids, including liensinine, isoliensinine, dauricine and cepharanthine, that function as novel inducers of autophagy
To verify whether the selected compounds were capable of inducing autophagy, we adopted the HeLa human cervical cancer cell line as a model for autophagy detection because it provided a discrete compartment for accurate immunofluorescence imaging analysis[22]
Summary
Betty Yuen Kwan Law, Wai Kit Chan, Su Wei Xu, Jing Rong Wang, Li Ping Bai, Liang Liu & Vincent Kam Wai Wong. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged organelles, and it recycles nutrients to maintain energy levels for cell survival. We have identified a group of natural alkaloid small-molecules that function as novel autophagic enhancers These alkaloids, including liensinine, isoliensinine, dauricine and cepharanthine, stimulated AMPK-mTOR dependent induction of autophagy and autophagic cell death in a panel of apoptosis-resistant cells. Enhancers of autophagy may play a protective role in cancer therapy by promoting autophagic cell death in tumours or by augmenting the efficacy of chemotherapeutic agents[6]. Autophagy may promote tumour growth by providing energy to poorly-vascularised cancer cells under hypoxic conditions or nutritional deprivation, autophagy-blocking molecules could be used in combination with chemotherapeutic agents to improve their therapeutic efficacy[7]
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