Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Abstract

Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan’s National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

Angelica Sinensis Polysaccharide Suppresses Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via a DANCR/AUF-1/FOXO3 Regulatory Axis

“…Accumulating evidence showed that ASP is useful for the treatment of various diseases, including cancers and ulcers, because of its anti-oxidative, anti-proliferative, and immunomodulatory effects [4]. For example, Liao et al demonstrated that ASP could prolong the survival rates of gastric cancer patients and cause cell death in gastric cancer cells by activating the intrinsic mitochondrial pathway [34]; Ye et al showed that ASP promoted gastric ulcer healing and reduced ulcer area of gastric [35]. Importantly, one study by Wang et al suggested that ASP was effective in treating and alleviating interstitial pulmonary fibrosis in rats, possibly by lowering collagen levels, inhibiting NF-κB activity, and downregulating TGF-β expression [36].…”

Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-benzylideneisobenzofuran-1(3H)-ones as Highly Potent antioxidants and Antiplatelet agents

“…In parallel, further developments were noticed when compounds 28m-q having electron-donating group (EDG) i.e., methyl groups at C-6 position of site I along with H/CH 3 /Cl/OMe groups at p-/m-position of site II were analyzed (Table 1, entry [13][14][15][16][17]. Compound 28m (IC 50 = 7.23 ± 0.04 μg/mL), electron-donating group (CH 3 group) at C-6 position of site I and no substitution at site II, displayed potential activity than ascorbic acid and showed greater activity than that of 28a (Table 1, Entry13).…”

“…Similarly, we analyzed the effect of EDG group at site I and prepared 28m-q having H/CH 3 /Cl/OMe groups at p-/m-position of site II (Table 1, entry [13][14][15][16][17]. Introduction of CH 3 group at site I (28m) showed more aggregation inhibitory activity (IC 50 = 47.93 ± 0.44 μg/mL) than 28a and less activity than 28g (Table 1, entry 13).…”

“…entry[14][15]. While 28p (IC 50 = 24.64 ± 0.42 μg/mL) with methyl (CH 3 ) group at C-6 position of site I and p-OMe substitutions on site II exhibited comparable activity; Compound 28p (IC 50 = 24.64 ± 0.42 μg/mL) with methyl (CH 3 ) group at C-6 position of site I and m-OMe substitutions on site II showed two-folds more potency than the standard reference(Table 1, entry…”

System Pharmacological Mechanism and Compatibility Laws of Jianghuang from Traditional Chinese Medicine In Blood-Regulating Formulae

“…Shen J et al [14] used RT-qPCR and western blot analysis to show that CX signi cantly decreased the Akt expression and activity, increased the activity of caspase-3, and was also shown to have anti-tumor effects in several types of cancer. DG can induce gastric cancer cell death through inhibiting mTOR protein and can signi cantly prolong the survival rate of cancer patients [15]. DG also affected a variety of apoptotic factors, Bcl-2 Associated X Protein (Bax), Bcl-2 and caspase-3 expression and promoted apoptosis in human breast cancer cells, therefore it has proved to be a promising therapeutic agent for breast cancer treatment [16].…”