Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3' diindolylmethane (DIM).
OBJECTIVE
Cancer chemoprevention is defined as the use of natural, synthetic, or biological agents to suppress, reverse or prevent the carcinogenic process from turning into aggressive cancer. Prostate apoptosis response-4 (Par-4) is a unique pro-apoptotic protein that selectively induces apoptosis in prostate cancer cells. However, its role in other malignancies has not been fully explored. This study tries to identify the functional significance of Par-4 in pancreatic cancer.


METHODS
Multiple molecular techniques such as Western blot analysis, trypan blue assay for cell viability, MTT assay for cell growth inhibition and Histone/DNA ELISA for apoptosis were used.


RESULTS
Western blot analysis revealed that 3,3'-diindolylmethane (DIM) a chemopreventive agent, specifically its more bioavailable formulation, B-DIM, at low doses (20 micromol/L) induces Par-4, in L3.6pl and Colo-357 pancreatic cancer cells. At similar doses, DIM reduced cell viability and caused cell growth inhibition and apoptosis. Moreover, DIM pre-treatment sensitized the cells to cytotoxic action of chemotherapeutic drug gemcitabine through up-regulation of Par-4.


CONCLUSIONS
The induction of Par-4 is indirectly related to increased sensitivity and cell death through apoptosis. To our knowledge the results reported here showed, for the first time, the induction of Par-4 by chemopreventive agents, in general, and DIM, in particular, in pancreatic cancer cells in vitro.
Azmi
Asfar Sohail
AS
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 9374 Scott Hall, 540 E Canfield, Detroit, Michigan 48201, USA.
Ahmad
Aamir
A
Banerjee
Sanjeev
S
Rangnekar
Vivek M
VM
Mohammad
Ramzi M
RM
Sarkar
Fazlul H
FH
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018179:Receptors, Thrombin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D000093542:Gemcitabine
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D007211:Indoles; D018179:Receptors, Thrombin; D003841:Deoxycytidine; C112908:protease-activated receptor 4; D002945:Cisplatin; C016392:3,3'-diindolylmethane; D000093542:Gemcitabine