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.