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Abstract
Esophageal squamous cell carcinoma (ESCC), a major histologic type of esophageal cancer, is one of the frequent causes of cancer-related death worldwide. Picropodophyllotoxin (PPT) is the main component of Podophyllum hexandrum root with antitumor activity via apoptosis-mediated mechanisms in several cancer cells. However, the underlying mechanism of the PPT effects in apoptosis induction in cancer remains ambiguous. Hence, in this study, we evaluate the anti-cancer effects of PPT in apoptotic signaling pathway-related mechanisms in ESCC cells. First, to verify the effect of PPT on ESCC cell viability, we employed an MTT assay. PPT inhibited the viability of ESCC cells in time- and dose-dependent manners. PPT induced G2/M phase cell cycle arrest and annexin V-stained cell apoptosis through the activation of the c-Jun N-terminal kinase (JNK)/p38 pathways. Furthermore, the treatment of KYSE 30 and KYSE 450 ESCC cells with PPT induced apoptosis involving the regulation of endoplasmic reticulum stress- and apoptosis-related proteins by reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, and multi-caspase activation. In conclusion, our results indicate that the apoptotic effect of PPT on ESCC cells has the potential to become a new anti-cancer drug by increasing ROS levels and inducing the JNK/p38 signaling pathways.
Highlights
An estimated 18,440 new cases and 16,170 deaths from esophageal cancer are projected in the United States in 2020 [1,2,3,4,5]
We report here that PPT induces apoptosis in Esophageal squamous cell carcinoma (ESCC) cells by reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress production, and Jun N-terminal kinase (JNK)/p38 activation
The effects of PPT on ESCC cell viability were investigated by an 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay
Summary
An estimated 18,440 new cases and 16,170 deaths from esophageal cancer are projected in the United States in 2020 [1,2,3,4,5]. The cyclolignan PPT, one of the aryl tetralin lignans, was launched as an anticancer drug targeting insulin-like growth factor 1 receptor (IGF-1R) [11]. It induces G2/M phase arrest and apoptosis in multiple myeloma cells by inhibiting IGF-1R [13]. JNK/p38 MAPK signaling pathways activation suppressed tumorigenesis and cancer growth by promoting cell death [18,19,20]. It is not clear whether JNK and p38-MAPK signaling are involved in PPT-induced cancer cell apoptosis. We report here that PPT induces apoptosis in ESCC cells by reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress production, and JNK/p38 activation
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