David E. Williams, PhD

Professor, Department of Environmental & Molecular Toxicology
Helen P. Rumbel Professor for Cancer Prevention
Linus Pauling Institute
Oregon State University, Corvallis, OR

 image of Dr. David Williams

Abstract: Cruciferous vegetables are a rich source of dietary indoles. Indole-3-carbinol (I3C), and 3,3’-diindolylmethane (DIM) are formed from glucobrassicin myrosinase found both in the plant and intestinal bacteria. I3C is unstable in the G.I. forming acid condensation products including DIM. We have studied cancer chemoprevention by dietary indoles in various models. Early work, led by Dr. George Bailey, established rainbow trout as a model for I3C chemoprevention of cancer. In the last decade we found supplementing diet of pregnant mice with I3C reduced offspring mortality from polycyclic aromatic hydrocarbon (PAH)-induced T-cell acute lymphoblastic leukemia (T-ALL). Immuno-compromised mice, injected with human T-ALL cells, had marked reduction in tumor growth when fed DIM. Studies in vitro with T-ALL cells displayed marked reductions in proliferation and viability along with enhanced apoptosis. We are now testing zebrafish embryos as a xenograft model for human T-ALL. Also, utilizing accelerator mass spectrometry (14C at atto-zeptomole range) we hope to test DIM and Brussels sprouts in enhancing metabolism and excretion of [14C]-PAHs when humans are “micro-dosed” at levels at or below daily exposures.

Early studies of cancer chemoprevention by indoles focused on “blocking” mechanisms. I3C and DIM inhibit enzymes that bioactivate carcinogens and induce detoxication enzymes thus reducing covalent DNA binding. I3C acid condensation products are aryl hydrocarbon receptor (AHR) ligands. AHR regulates many important pathways including cell cycle, apoptosis, autophagy, angiogenesis, oxidative stress and chronic inflammation. Currently, we are assessing epigenome modulation and cancer chemoprevention. I3C and DIM inhibit histone deacetylases (HDACs), alter chromatin structure, expression of select microRNAs and methylation status of promoter regions of genes involved in carcinogenesis. Epidemiology studies consistently show an inverse correlation between cruciferous vegetable intake and cancer incidence. However, clinical intervention trials have been somewhat disappointing. The potential for indole supplements in chemoprevention of cancer in humans is still an open question.

(Supported by PHS NIH grants ES00210, ES03850, ES04766, ES013534, CA90890 and others).