Cantharidin induces apoptosis through the calcium/PKC-regulated endoplasmic reticulum stress pathway in human bladder cancer cells
Journal
American Journal of Chinese Medicine
Journal Volume
43
Journal Issue
3
Pages
581-600
Date Issued
2015
Author(s)
Abstract
Bladder cancer is a common malignancy worldwide. However, there is still no effective therapy for bladder cancer. In this study, we investigated the cytotoxic effects of cantharidin [a natural toxin produced (pure compound) from Chinese blister beetles (Mylabrisphalerata or Mylabriscichorii) and Spanish flies (Cantharis vesicatoria)] in human bladder cancer cell lines (including: T24 and RT4 cells). Treatment of human bladder cancer cells with cantharidin significantly decreased cell viability. The increase in the expressions of caspase-3 activity and cleaved form of caspase-9/-7/-3 were also increased in cantharidin-treated T24 cells. Furthermore, cantharidin increased the levels of phospho-eIF2α and Grp78 and decreased the protein expression of procaspase-12, which was accompanied by the increase in calpain activity in T24 cells. Cantharidin was capable of increasing the intracellular Ca2+ and the phosphorylation of protein kinase C (PKC) in T24 cells. The addition of BAPTA/AM (a Ca2+ chelator) and RO320432 (a selective cell-permeable PKC inhibitor) effectively reversed the increase in caspase-3 and calpain activity, the phosphorylation levels of PKC and eIF2α and Grp78 protein expression, and the decrease in procaspase-12 expression induced by cantharidin. Importantly, cantharidin significantly decreased the tumor volume (a dramatic 71% reduction after 21 days of treatment) in nude mice xenografted with T24 cells. Taken together, these results indicate cantharidin induced human bladder cancer cell apoptosis through a calcium/PKC-regulated ER stress pathway. These findings suggest that cantharidin may be a novel and potential anticancer agent targeting on bladder cancer cells. ? 2015 World Scientific Publishing Company & Institute for Advanced Research in Asian Science and Medicine.
Subjects
Bladder Cancer Cells; Calcium; Cantharidin; ER Stress; PKC
SDGs
Other Subjects
calcium; calpain; cantharidin; caspase; caspase 12; caspase 3; caspase 7; caspase 9; glucose regulated protein 78; initiation factor 2alpha; procaspase 12; protein kinase C; unclassified drug; antineoplastic agent; calcium; cantharidin; caspase 3; protein kinase C; animal experiment; animal model; antineoplastic activity; apoptosis; Article; beetle; bladder cancer; bladder cancer cell line; calcium cell level; cancer cell; cancer therapy; Cantharis vesicatoria; cell viability; Diptera; drug cytotoxicity; endoplasmic reticulum stress; enzyme activity; enzyme linked immunosorbent assay; enzyme phosphorylation; human; human cell; male; mouse; MTT assay; Mylabriscichorii; Mylabrisphalerata; nonhuman; protein expression; protein phosphorylation; regulatory mechanism; therapy effect; tumor volume; tumor xenograft; Western blotting; animal; apoptosis; Bagg albino mouse; bladder tumor; drug effects; endoplasmic reticulum stress; genetics; metabolism; nude mouse; papilloma; pathology; physiology; signal transduction; tumor cell line; upregulation; Animals; Antineoplastic Agents; Apoptosis; Calcium; Cantharidin; Caspase 3; Cell Line, Tumor; Endoplasmic Reticulum Stress; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Papilloma; Protein Kinase C; Signal Transduction; Up-Regulation; Urinary Bladder Neoplasms
Type
journal article