<p>Anisodamine Suppressed the Growth of Hepatocellular Carcinoma Cells, Induced Apoptosis and Regulated the Levels of Inflammatory Factors by Inhibiting NLRP3 Inflammasome Activation</p>

Abstract

Introduction: Hepatocellular carcinoma (HCC) is a primary liver cancer with a 5-year incidence of over 70%. Anisodamine (ANI), an alkaloid extracted from Anisodus, has a good therapeutic effect in septic shock and morphine addiction. Our study designed to investigate the anticancer effect of anisodamine (ANI) on HCC. Materials and Methods: HepG2 cells were subcutaneously injected into BALB/C nude mice and the tumor tissue was subcutaneously inoculated to construct the transplanted tumor. Mice were randomly divided into 10 groups (n = 5): control group, ANI-10 group, ANI-50 group, ANI-200 group, ANI-200+pcDNA-NLRP3 group, ANI-200+EV group, sh-NLRP3 group, ANI-200 + sh-NLRP3 group, normal group and normal+ANI-200 group. Results: Studies indicated that ANI inhibited the growth of HCC xenografts and reduced liver damage in a dose-dependent manner. Besides, ANI increased the survival rate of tumorbearing mice and suppressed the expression of NLRP3 in a dose-dependent manner. It is worth noting that NLRP3 overexpression reversed the inhibitory effect of ANI on HCC xenografts. In addition, TUNEL analysis showed that ANI-induced apoptosis of tumor cells, and NLRP3 overexpression reversed the inhibitory effect of ANI on HCC. Moreover, ANI further regulated the levels of IFN-γ, TNF-α, IL-4 and IL-27. Notably, low expression of NLRP3 enhanced the inhibitory effect of ANI on the development of HCC xenografts in mice. Discussion: These findings indicate that ANI suppressed the growth of HCC cells, induced apoptosis and regulated the levels of inflammatory factors by inhibiting NLRP3 inflammasome activation.

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

“…Different inhibitory compounds such as luteoloside and anisodamine have been shown to have antitumoral activity in vitro and in vivo, including the suppression of cell proliferation and the impairment of cell migration and invasion [ 168 , 169 ]. Further investigations are needed to better understand the precise mechanisms underlying inflammasome activation and to design inflammasome-directed therapies for CLD and HCC.…”

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

“…Furthermore, berberine exerted anticancer activity via targeting variant pathways, such as NF-κB/COX-2, p38/JNK, AP-2/telomerase reverse transcriptase (hTERT), cytochrome-c/caspase, and HIF-1α/VEGF signaling in human gastric and NSCLC cell lines ( 259 , 260 ). The alkaloid anisodamine ( Figure 6 ) is another anticancer compound that inhibited the growth, invasion, and proliferation of HepG2 cells and suppressed the expression and activation of IFN-γ, IL-27, NLRP3, IL-4, and TNF-α ( 261 ). In a similar study, a steroidal alkaloid, cyclopamine ( Figure 6 ), induced apoptosis and suppressed the proliferation of HEL and TF1a cells via induction of PKC, COX-2 overexpression, PARP cleavage, and modulation of MAPK/Akt signaling ( 262 ).…”

What role does pyroptosis play in cancer?

“…Wei et al. conducted an ex vivo study and found that the downregulation of the NLRP3 inflammasome was associated with the genesis and development of HCC [ 81 , 82 ]. Additionally, Wei et al.…”

“…(B) The pathway of different cancers. Cancer type Level of pyroptotic components Associated consequences References (A) Esophagus cancer NLRP3↑ cell death and Barrett's esophagus [ 61 ] Upregulated GSDME transit the apoptosis to pyroptotic-signaling pathways [ 60 ] Gastric cancer GSDMD↓ cancer cell proliferation [ 62 ] GSDMA↓ anti-oncogenic factor [ 70 , 71 ] GSDMB↑ control tumor infringement [ 49 ] GSDMC cancer suppressor gene [ 73 ] DFNA5/GSDME signaling pathway pyroptosis facilitates GC progression [ 62 ] Hepatocellular carcinoma Caspase-1 protein↓ Tumor proliferation [ 80 , 84 ] NLRP3↓ Increase HCC etiology and progression [ 81 , 82 ] AIM2↑ Promote pyroptosis and antitumor effects [ 85 , 87 ] Colorectal cancer Caspase-1↑ Promote epithelial cell proliferation and apoptosis [ 54 ] Lack of AIM2 Poor prognosis in CRC [ 89 ] NLRP1↓ Tumor progression [ 88 , 91 ] GSDMC↓ Tumor cell proliferation ...…”