Magic traditional Chinese medicine ingredients generated autophagic flux to suppress tumor progression and novel combination therapy strategy in gastric cancer

SCIENCE CHINA PRESS

IMAGE: ACTIVATION OF BECLIN-1 BY PICEATANNOL PROMOTES AUTOPHAGIC FLUX IN GC CELLS, AND COMBINED WITH EVEROLIMUS, TRIGGERS AUTOPHAGIC DEATH, ULTIMATELY INHIBITING TUMOR PROGRESSION, AND PROVIDING A NEW APPROACH TO GC TREATMENT.

CREDIT: ©SCIENCE CHINA PRESS

This study is led by Dr. Longtao Huangfu, and Dr. Xiaoyang Wang (Peking University Cancer Hospital & Institute). A diet of fresh fruits and vegetables may reduce the prevalence of cancers, including GC (Eusebi et al., 2020; Liu et al., 2021). In addition, clinical studies have found that certain biologically active dietary molecules can inhibit multiple steps in the pathways associated with carcinogens (Arai and Nakajima, 2020). Piceatannol (trans-3,4,3ʹ,5ʹ-tetrahydroxystilbene), an analog of resveratrol, is a naturally occurring polyphenolic compound present in approximately 70 plant sources, including passion fruit, rhubarb, and legumes (Banik et al., 2020; Seyed et al., 2016). This compound was first reported as a bioactive antitumor molecule in 2003 (Larrosa et al., 2004). Subsequent reports indicated that piceatannol affects diverse pathways and exerts an antitumor effect on several types of cancer, including colorectal cancer, lung cancer, and lymphoma (Cao et al., 2020; Nayyab et al., 2020). Hence, piceatannol may be an effective drug for GC treatment. Indeed, investigating the effects induced by its comparative bioactive properties have become a focus in relevant research fields.

The research team found that piceatannol as a potential targeting agonist of Beclin-1, to assess its efficacy as an antitumor agent against GC. To this end, this group employs multiple human GC cell lines as well as a murine xenograft model. Results show that piceatannol inhibits cell proliferation and enhances autophagic activity in GC cells. Moreover, piceatannol is found to directly target Beclin-1 by inhibiting its phosphorylation at Ser-295, a canonical locus for the negative regulation of autophagic activity, thus, increasing autophagic flux through the Beclin-1-dependent pathway in GC cells. This team analyzed the synergistic antitumor activity of compounds known to regulate and interact with the Beclin-1 network. Collectively, this research suggested that piceatannol, in combination with the mTOR inhibitor, everolimus, exhibits strong synergistic effects over a wide range of dose responses, proving to be an attractive therapeutic strategy for GC.