3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer.
Clinical management of pancreatic cancer is a major problem, which is in part due to both de novo and acquired resistance to conventional therapeutics. Here, we present in vitro and in vivo preclinical evidence in support of chemosensitization of pancreatic cancer cells by 3,3-diindolylmethane (DIM), a natural compound that can be easily obtained by consuming cruciferous vegetables. DIM pretreatment of pancreatic cancer cells led to a significantly increased apoptosis (P < 0.01) with suboptimal concentrations of chemotherapeutic agents (cisplatin, gemcitabine, and oxaliplatin) compared with monotherapy. It is known that resistance to chemotherapy in pancreatic cancer is associated with constitutively activated nuclear factor-kappaB (NF-kappaB), which becomes further activated by chemotherapeutic drugs. Our data provide mechanistic evidence for the first time showing that DIM potentiates the killing of pancreatic cancer cells by down-regulation of constitutive as well as drug-induced activation of NF-kappaB and its downstream genes (Bcl-xL, XIAP, cIAP, and survivin). Most importantly, using an orthotopic animal model, we found reduction in tumor size (P < 0.001) when DIM was given in combination with oxaliplatin compared with monotherapy. This was accompanied by loss of phospho-p65 and down-regulation of NF-kappaB activity and its downstream genes (Bcl-xL, survivin, and XIAP), which correlated with reduced cell proliferation (as assessed by Ki-67 immunostaining of tumor specimens) and evidence of apoptosis [as assessed by poly(ADP-ribose) polymerase cleavage and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining]. These results provide strong in vivo evidence in support of our hypothesis that DIM could abrogate chemotherapeutic drug (cisplatin, gemcitabine, and/or oxaliplatin)-induced activation of NF-kappaB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics.
Banerjee
Sanjeev
S
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Wang
Zhiwei
Z
Kong
Dejuan
D
Sarkar
Fazlul H
FH
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D007211:Indoles; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D045304:Cytochromes c; D002945:Cisplatin; C016392:3,3'-diindolylmethane; D000093542:Gemcitabine