Autophagy, also known as macroautophagy, is a tightly regulated process involved in the stress responses, such as starvation. It is a vacuolar, lysosomal pathway for the degradation of damaged proteins and organelles in eukaryotic cells. Autophagy also plays a key role in various tissue processes and immune responses and in the regulation of inflammation. Over the past decade, three levels of autophagy regulation have been identified in mammalian cells: 1) signaling, 2) autophagosome formation, and 3) autophagosome maturation and lysosomal degradation. Any deregulation of the autophagy processes can lead to the development of diverse chronic diseases, such as diabetes, obesity, cardiovascular disease, neurodegenerative disease, and malignancies. However, the potential role of autophagy in cancer is rather complex and has been associated with both the induction and the inhibition of neoplasia. Several synthetic autophagy modulators have been identified as promising candidates for cancer therapy. In addition, diverse phytochemicals derived from natural sources, such as curcumin, ursolic acid, resveratrol, thymoquinone, and γ‐tocotrienol, also have attracted attention as promising autophagy modulators with minimal side effects. In this review, the authors discuss the importance of autophagy regulators and various natural compounds that induce and/or inhibit autophagy in the prevention and therapy of cancer.
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.31978
Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity https://www.oncotarget.com/article/20767/text/
Autophagy is a cellular bulk degradation pathway implicated in various diseases. Inhibition of autophagy has been regarded as a new therapeutic strategy for cancer treatment, especially in combination with chemotherapy. In our study, we identified two natural compounds, dauricine (DAC) and daurisoline (DAS), as two potent autophagy blockers through a high-content screening. DAC and DAS are alkaloids isolated from traditional Chinese medicine Rhizoma Menispermi. We systematically examined the effects of DAC and DAS on autophagy function in HeLa cells and found that DAC and DAS induced massive formation of autophagic vacuoles and lipidation of LC3. The accumulation of autophagic vacuoles and LC3 lipidation are due to blockage of autophagosome maturation as evidenced by interrupted colocalization of autophagsosome and lysosome, increased GFP-LC3/RFP-LC3 ratio and accumulation of autophagic substrate p62. Moreover, DAC and DAS impaired lysosomal function, as indicated by reduced lysosomal protease activity and increased lysosomal pH values. Importantly, we showed that DAC and DAS strongly inhibited the lysosome V-type ATPase activity. For the therapeutic potential, we found that DAC and DAS blocked the campothecin (CPT)-induced protective autophagy in HeLa cells, and dramatically sensitized the multiple cancer cells to CPT-induced cell death. In conclusion, our result shows that DAC and DAS are autophagy inhibitors which inhibit the lysosomal degradation of auophagic vacuoles, and sensitize the CPT-induced cancer cell death. The study implies the therapeutic potential of DAC and DAS in the treatment of cancers in combination of chemotherapy by inhibiting autophagy.
EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC
Background
Several EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib (Gef), have been used as effective clinical therapies for patients with non-small cell lung cancer (NSCLC). However, due to acquired resistance, the efficacy of Gef treatment is severely blocked. Our preliminary study found that epigallocatechin gallate (EGCG) in combination with Gef could work synergistically to increase the sensitivity to Gef in NSCLC, but the mechanisms responsible for this have not been completely defined.
Purpose
In our present study, we devoted to investigate the synergistic effects of combined EGCG and Gef treatment and the importance of autophagy and ERK signaling pathway in overcoming acquired drug resistance to Gef in NSCLC.
Methods
We evaluated the synergistic effects of combined EGCG and Gef treatment through in vitro cell proliferation/viability assays and in vivo xenograft studies, respectively. Autophagic flux was assessed by GFP-microtubule-associated protein 1 light chain 3 (LC3) plasmid transfection and western blot detection of autophagy-related proteins. Besides, the role of ERK on acquired resistance was validated with a ERK inhibitor.
Results
We discovered that EGCG can synergize with Gef to inhibit the proliferation of Gef-resistant NSCLC cells and suppress tumor growth in a xenograft mouse model. The underlying mechanisms of synergism were investigated, and the results showed that co-treatment with Gef and EGCG could inhibit Gef-induced autophagy and ERK phosphorylation. Consistently, the expression of LC3-II/I and ATG5 were inhibited, whereas the expression of p62 was enhanced in EGCG and Gef combination treatment groups. Further, inhibition of autophagy in Gef-resistant A549 cells could augment cell death.
Conclusion
In conclusion, EGCG overcomes Gef resistance by inhibiting autophagy and augmenting cell death through targeting ERK pathway in NSCLC. Gef and EGCG combination therapy may be an effective strategy to overcome acquired resistance in NSCLC.
