Data from 3,3′-Diindolylmethane Enhances Chemosensitivity of Multiple Chemotherapeutic Agents in Pancreatic Cancer

Abstract

<div>Abstract<p>Clinical management of pancreatic cancer is a major problem, which is in part due to both <i>de novo</i> and acquired resistance to conventional therapeutics. Here, we present <i>in vitro</i> and <i>in vivo</i> 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 (<i>P</i> < 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-κB (NF-κB), 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-κB and its downstream genes (Bcl-xL, XIAP, cIAP, and survivin). Most importantly, using an orthotopic animal model, we found reduction in tumor size (<i>P</i> < 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-κB 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) polymease cleavage and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining]. These results provide strong <i>in vivo</i> evidence in support of our hypothesis that DIM could abrogate chemotherapeutic drug (cisplatin, gemcitabine, and/or oxaliplatin)–induced activation of NF-κB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5592–600]</p></div>