Plumbagin, isolated from Plumbago zeylanica, induces cell death through apoptosis in human pancreatic cancer cells.
OBJECTIVE
Pancreatic cancer is one of the most resistant malignancies. Several studies have indicated that plumbagin isolated from Plumbago zeylanica possesses anticancer activity. However, its antitumor effects against pancreatic cancer have not been explored.


METHODS
We investigated the effect of plumbagin on the growth of human pancreatic carcinoma cells and its possible underlying mechanisms.


RESULTS
Plumbagin inhibited the growth of Panc-1 and Bxpc-3 cells in a dose-dependent and time-dependent manner. Liu's staining and transmission electron microscopy demonstrated morphological changes resembling apoptosis in Panc-1 cells treated with plumbagin. The degree of apoptosis was assessed by measuring the proportions of sub-G(1), annexin V+/propidium iodide-, and terminal- deoxynucleotidyl-transferase-mediated-nick-end labeling (TUNEL)+ cells, and a significant increment in apoptotic cells was observed. Exposure to plumbagin caused the upregulation of Bax, a rapid decline in mitochondrial transmembrane potential, apoptosis-inducing factor overexpression in cytosol, and the cleavage of procaspase-9 and poly ADP-ribose polymerase. Activation of caspase-3, but not caspase-8, was evidenced by fluorometric substrate assay. Pretreatment with caspase inhibitors did not block plumbagin-induced apoptosis. Alternatively, it is possible that plumbagin downregulated phosphoinositide 3-kinase activity through a negative feedback mechanism. In an orthotopic pancreatic tumor model, plumbagin markedly inhibited the growth of Panc-1 xenografts without any significant effect on leukocyte counts or body weight.


CONCLUSIONS
Plumbagin may induce apoptosis in human pancreatic cancer cells primarily through the mitochondria-related pathway followed by both caspase-dependent and caspase-independent cascades. It indicates that plumbagin can be potentially developed as a novel therapeutic agent against pancreatic cancer.
Chen
Chien-An
CA
Department of Radiation Oncology, Far Eastern Memorial Hospital, Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan.
Chang
Hen-Hong
HH
Kao
Chung-Yu
CY
Tsai
Tung-Hu
TH
Chen
Yu-Jen
YJ
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000302:isolation & purification / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D029606:Plumbaginaceae / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000378:metabolism
D000970:Antineoplastic Agents; D009285:Naphthoquinones; D051028:bcl-2-Associated X Protein; D020169:Caspases; C014758:plumbagin