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

Abstract

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-KB (NF-KB), 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-KB 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 downregulation of NF-KB 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 in vivo evidence in support of our hypothesis that DIM could abrogate chemotherapeutic drug (cisplatin, gemcitabine, and/or oxaliplatin)-induced activation of NF-KB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5592-600]

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

“…Thus, it is important to identify agents that can be used in combination with sorafenib. Multiple naturally occurring compounds from diets or medicinal plants can modulate different cellular survival pathways, thus potentiating the anticancer activity of drugs used in anticancer therapy (23,24). One of such compounds is wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid derived from the root of the medicinal herb Scutellaria baicalensis Georgi (25).…”

Inhibitory effect of the low‑toxic exogenous aryl hydrocarbon receptor modulator 3'3‑diindolylmethane on gastric cancer in mice

“…It has been verified that DIM can induce apoptosis in colon (19), breast (20), pancreatic (21,22) and lung cancer cells (27), among other types. In prostate cancer cells, DIM inhibits the AKT signaling pathway and induces cell apoptosis (28).…”

“…DIM has been identified as an anti-cancer agent involved in various solid malignancies, including ovarian (12), prostate (13), colon (14) and pancreatic cancer (15). The anti-cancer effects of DIM include suppressing cancer cell proliferation (16)(17)(18) and promoting cancer cell apoptosis (19)(20)(21). There have been few reports to date regarding the effects of DIM on GCa cells, and the purpose of the present study was to examine the potential beneficial effect of DIM in the prevention of tumor development following the subcutaneous transplantation of SGC-7901 cells into mice, in addition to exploring the possible underlying mechanisms.…”

Indoles as anticancer agents

“…Their cytotoxicity indicates that they could be motivating as prospective antitumoral chemotherapeutics [79,80] . Indoles (I3C and DIM or its derivatives) have been revealed to induce apoptosis in breast [81][82][83][84][85][86][87] , squamous cell carcinoma [88] , cholangiocarcinoma [89] , colon [90][91][92][93] , cervical [94] , ovarian [95] , pancreatic [96,97] and prostate [98][99][100][101] cancer cells. Many other indole derivatives that were reported as active anti-cancer agents as follow: the potential prodrug (1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-trideuteronmethylaminome thyl)-5-methoxyindole-4,7-dione), pentamethylmelamine (PMM) in which the labeled pentamethylmelamine is attached to an indole-4,7-dione moiety has attracted much interest as an anti-tumor agent for over 35 years ( Figure 11).…”