Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

Abstract

Background/aims Isoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown. Methods In current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects. Results IATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo. Conclusions IATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

Target c-Myc to treat pancreatic cancer

“…Aberrant activation of different signaling pathways is involved in the pathogenesis of pancreatic cancer. 64 Additionally, inhibition of these proliferative signals showed satisfactory efficacy in preclinical studies of pancreatic cancer. 64 As mentioned previously, KRAS mutation is a major propellant for the initiation and progression of pancreatic cancer.…”

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…Apart from IAL [ 202 ], recently particularly ALT has been extensively studied for its cytotoxic and anti-proliferative activity in a variety of human cancer cell lines, including the colon [ 203 ], lung [ 204 ], breast [ 205 ], gastric [ 206 ], pancreatic cancer [ 207 ], leukemia [ 208 ], and glioblastoma multiforme [ 209 ]. The anti-tumor properties of ALT occurred through a wide range of overlapping molecular pathways, interacting with each other [ 180 , 207 ].…”

Induction of Apoptosis by Isoalantolactone in Human Hepatocellular Carcinoma Hep3B Cells through Activation of the ROS-Dependent JNK Signaling Pathway

“…Moreover, a recent study showed that IALT increased phosphorylation of p38 and JNK in breast cancer cells, but not in normal breast cells, and IALT-mediated apoptosis could be abolished by inhibitors of p38 and JNK [ 45 ]. In addition, several previous studies have shown that an increase in ROS production was involved in IALT-induced apoptosis in various types of cancer cells [ 40 , 42 , 43 , 48 , 49 ]. Therefore, we assessed whether the IALT-induced apoptosis of Hep3B cells was related to ROS and investigated the role of ROS in the activation of the MAPK signaling pathway.…”

“…IALT has also been extensively reported to exert anti-cancer effects by inducing apoptosis, cell cycle arrest and autophagy in several types of cancer cells, which was confirmed to be selective for cancer cells [ 36 , 37 , 38 , 39 ]. Mechanistically, activation or inhibition of various cellular signaling pathways, including nuclear factor-κB, phosphatidylinositol 3-kinase/Akt, and MAPK, and increased ROS production were found to be involved in the induction of IALT-induced cancer cell apoptosis [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. However, the anti-cancer effects of IALT on HCC cells have not been studied yet.…”