Piperlongumine induces autophagy in biliary cancer cells via�reactive oxygen species-activated Erk signaling pathway

Abstract

Biliary cancer (BC) is an aggressive neoplasm with high mortality. BC can be categorized into three groups: Intrahepatic cholangiocarcinoma (CCA; also known as bile duct cancer), extrahepatic cholangiocarcinoma and gallbladder cancer. Due to its heterogeneity and aggressiveness, the response to current chemotherapy and radiotherapy methods in patients with BC is poor. Therefore, there is an urgent requirement to develop drugs to treat BC. Piperlongumine (PL), a naturally occurring small molecule isolated from Piper longum L., exhibits anticancer activity by inducing reactive oxygen species (ROS) production. In the present study, the effects of PL on cell proliferation, cell cycle, apoptosis and autophagy in BC cells were investigated. PL induced BC cell death in a concentration- and time-dependent manner by inducing ROS production. PL induced cell cycle arrest in CCA cells (HuCCT-1) and gallbladder cancer cells (OCUG-1) cells, but with distinct cell cycle distribution profiles. PL caused G2/M cell cycle arrest in HuCCT-1 cells, and G0/G1 cell cycle arrest in OCUG-1 cells. PL induced apoptosis and autophagy; PL treatment induced accumulation of LC3-II in a concentration- and time-dependent manner. The Erk signaling pathway appeared to be involved in autophagy induction. Application of the ROS scavenger, N-acetyl-l-cysteine, to BC cells attenuated the cell death, cell cycle arrest, apoptosis and autophagy induced by PL treatment. These findings indicated that PL may be a potential agent for BC treatment in the future.

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…Four natural compounds have been recently described to induce CCA cell death, implicating the activation of autophagy as a mediator of their cytotoxic effects:piperlongumine (small molecule extracted from Piper longum plant [151]), pterostilbene (an active constituent of blueberries [152]), pristimerin (a triperpenoid isolated from Maytenus heterophylla [153]) and dihydroartemisinin (an active compound found in Artemisia annua [154]). Although it has been proven that autophagy induction is necessary for their mechanism of action, the specific molecular mechanisms governing their autophagy modulation abilities are not fully understood yet.…”

“…Although it has been proven that autophagy induction is necessary for their mechanism of action, the specific molecular mechanisms governing their autophagy modulation abilities are not fully understood yet. Piperlongumine induced apoptosis [155] and autophagy [151] in CCA cells through the production of ROS, induction of ER stress and activation of JNK-ERK signaling pathway [151]. Similar to piperlongumine, dihydroartemisinin is an antimalaria drug that induces ROS-mediated ER stress through DAPK activation, promoting the disruption of Beclin1-Bcl-2 complex and inducing autophagy-mediated CCA cell death, therefore activating initiation of autophagy.…”

Antitumor Efficacy of the Herbal Recipe Benja Amarit against Highly Invasive Cholangiocarcinoma by Inducing Apoptosis both In Vitro and In Vivo

“…Previous reports have shown that various plant extracts can induce both apoptosis and autophagy in CCA cells [24,39]. According to our current results, BJA could induce apoptosis in KKU-213 cells; therefore, the other mode of action via autophagy was investigated.…”

“…Previous studies have shown that autophagy is considered as another response mechanism of CCA to several chemotherapy treatments [ 24 , 25 , 26 ]. Hence, in order to determine the effect of BJA-95 on the autophagy induction in CCA, autophagic vacuoles were imaged by fluorescence microscopy ( Figure 4 A) and were then quantitated by flow cytometry ( Figure 4 B).…”

Naturally occurring Piper plant amides potential in agricultural and pharmaceutical industries: perspectives of piperine and piperlongumine

“…Induction of ROS by piperlongumine purportedly occurs by activation of the Erk signaling pathway, and has been shown to induce cell cycle arrest in cholangiocarcinoma cells (HuCCT-1) and gallbladder cancer cells (OCUG 1). Piperlongumine also caused G2/M cell cycle arrest in HuCCT 1 cells and G0/ G1 cell cycle arrest in OCUG 1 cells [29]. Still another study showed an increase in the sensitivity of colorectal cancer cells in association with changes to ROS homeostasis due to inhibition of glutathione production and thioredoxin function by treatment with piperlongumine [30].…”