Could you introduce your current research into prostate cancer?

My work examines how environmental contaminants interact with the synthesis and metabolism of steroid hormones to disrupt the endocrine systems of exposed humans or wildlife. At present, I am investigating the potential protective properties of natural compounds against prostate cancer. I find this disease interesting because its aetiology and subsequent progression to a drug-resistant, hormone-independent, and often deadly form, is not well understood. Dietary factors appear to play a larger role in the risk of developing prostate cancer than other endocrine cancers – no clear genetic predispositions have yet been established.

The main goal of my current project is therefore to determine exactly how natural compounds convey this kind of protection at the molecular level: what are the mechanisms of action in the prostate cancer cell that cause these natural compounds to kill them whilst leaving normal cells alone? Do they block androgen production by inhibiting steroidogenic enzymes? Do they reduce the growth-stimulatory actions of androgens by blocking their receptor? Or are they killing the cells via entirely different cellular pathways that do not respond in normal prostate cells?

What are the benefits of diindolylmethane (DIM) and how can its levels be increased in the body?

DIM is formed in the acidic conditions of the stomach as a condensation product of indole-3-carbinol – found in high quantities in cruciferous vegetables of the Brassica family, such as broccoli, cabbage, cauliflower, Brussels sprouts and kale. DIM has been shown to have a plethora of beneficial effects: it is an antioxidant, reduces inflammation, stimulates immune responses, protects

against DNA damage and is effective against the growth of cancers of various origins.

How can you increase your intake of DIM? Listen to your mother and eat your vegetables! Unfortunately, Western dietary lifestyles are not conducive to high vegetable intake, despite the constant availability of fresh produce. The pervasiveness of cheaper, highly processed and otherwise manipulated food products has resulted in such foods becoming the diet of choice for a significant proportion of the Western population.

Prostate cancer frequently progresses into a hormone-independent form that is difficult to treat and frequently results in death. In what ways can DIM improve this ordinarily uncontrollable scenario?

DIM-containing foods may act chemopreventively; in other words, if you eat a healthy diet with lots of vegetables, fruits, few processed foods and little red meat, you avoid the initial formation of prostate cancer cells and thus reduce your risk of developing a tumour. This is because compounds such as DIM are effective at killing cancer cells at the very early initiation stage.

At the other end of the spectrum, once diagnosed with a tumour, DIM may effectively destroy prostate cancer cells that are not treatable by conventional chemotherapeutic agents, or can be used in combination with other chemotherapeutics in an adjuvant formulation to enhance overall therapeutic effectiveness.

Can you elaborate on some of the biggest challenges you have faced in this investigation? How were you able to overcome these?

Obtaining – and keeping – research funding has been very challenging. Another obstacle

was finding high-quality graduate students to work on the project. This often causes a delay in the starting date and subsequent progress of the work. We have been fortunate, however, to remain relatively uninfluenced by any technical difficulties. Although the DIM project has taken a different direction from what was initially proposed, it has resulted in more interesting, unexpected findings that will open up novel avenues for future research.

To what extent do you expect your findings to inform further study and impact clinical best practice?

By elucidating novel targets for natural compounds in the cancer cell, avenues are opened for the development of new and more potent/efficacious anticancer molecules that specifically block/activate those targets and kill the cancer cells.

How do your other research projects, such as the investigation of endocrine-disrupting effects of pesticides/environmental contaminants, overlap?

Many of the basic principles are the same. Chemicals in the environment that affect the endocrine system at critical moments, such as during foetal development or puberty, may pose risks to human health (and wildlife). On the other hand, chemicals that can effectively disrupt hormone action in a clinical setting may be beneficial in treating hormone-dependent cancers. To a toxicologist, gaining a better understanding of how healthy or cancerous cells die are of equal interest and follow the same principles.

Toxicologist Dr Thomas Sanderson discusses the link between diet and prostate cancer risk, and provides an insight into his investigations on the protective properties of natural compounds

The bright side of a DIM diet

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DR THOMAS SANDERSON

THERE HAVE BEEN growing concerns in recent years regarding the health risks posed by various chemical pesticides, drugs and other environmental contaminants capable of influencing the endocrine systems of exposed humans and wildlife. At the INRS-Institut Armand-Frappier in Quebec, Canada, toxicologist Dr Thomas Sanderson is investigating the effects of these hormone-disrupting chemicals on enzyme expression and function within steroid biosynthesis and their relation to endocrine disruption and hormone-dependant cancer onset and pathogenesis. Sanderson and the research team he leads have been carrying out studies in this area for almost a decade, supported in their important work by generous grants from funding agencies including the Natural Science and Engineering Research Council of Canada (NSERC), California Breast Cancer Research Program (CBCRP) and Canadian Institutes of Health Research (CIHR).

Specifically, Sanderson’s team is conducting cutting-edge research across three overlapping areas. Firstly, the group is investigating the endocrine-disrupting effects of pesticides and other environmental contaminants; secondly, it is developing cell-based bioassays for the identification of these chemicals (as well

as a wider range of medical and consumer products); and thirdly, the Sanderson lab is exploring the potential therapeutic or protective effects of certain natural compounds, particularly in relation to prostate cancer.

COMBATING CANCER AT THE CELLULAR LEVEL It is this third area that Sanderson and his colleagues – Drs Stephen Safe of Texas A&M, USA, and Emma Guns of The Prostate Centre, Canada – are currently devoting much of their time to, as part of a CIHR-funded project aimed at elucidating the potential anticancer properties of the compound diindolylmethane (DIM) and its synthetic derivatives (ring-DIMs). DIM is formed in the stomach as a natural metabolite of indole-3-carbinol, which is found in high quantities in cruciferous vegetables of the Brassica family. Previous epidemiological studies have indicated that high consumption of these foods is associated with a protective effect against certain cancers, while in vivo and in vitro studies have shown that DIM inhibits tumour growth, including those of the prostate.

Prostate cancer is the leading cause of cancer-related death among men in the developed world. It is therefore unsurprising

that Sanderson and his team want to better understand the anti-androgenic and anti-proliferative effects of DIM and ring-DIM on prostate cancer cells. Furthermore, prostate cancer is of particular interest to Sanderson and his team in part due to the important role played by androgenic hormones in its pathogenesis. Prostate tumours are usually initially dependent on androgens to grow, at which point they can generally be

treated successfully with androgen receptor (AR) antagonists. With time, however, prostate tumours can become androgen-independent; when this occurs, AR antagonists are no longer effective and patient morbidity and mortality increases significantly. To address this, Sanderson and his team have found that ring-DIMs may provide a novel therapeutic solution for prostate cancer at both of these stages: their research has shown that ring-DIMs can not only inhibit cell growth in androgen-dependant cancer cells, but also induce cell death in androgen-independent tumour cells by disrupting mitochondrial function. In addition, the group’s in vitro cell line studies have found that ring-DIMs possess more potent anticancer properties than DIM itself, and are cytotoxic to cancer cells at concentrations that do not affect healthy ones.

These discoveries have led the Sanderson lab to initiate in vivo investigations of the mechanisms involved. The team is using mice carrying bioluminescent human prostate cancer cells (xenografts) to enable in vivo

At the INRS-Institut Armand-Frappier in Canada, work is underway to determine exactly when and how compounds from the external environment can influence the endocrine systems of exposed humans and wildlife

Exposure answers

Is the docking of this DIM derivative in the protein calcium-dependent calmodulin kinase II (CaMKII) responsible for mitochondrial toxicity and killing prostate cancer cells?

Dr Thomas Sanderson is confident that his basic research will pave the way for future major medical advances and a better understanding of the risks of exposure to environmental contaminants

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imaging and monitoring of tumour location and growth. The group is also conducting parallel experiments using prostate cancer cell lines in culture in order to better elucidate the anticancer mechanisms at play. There are still many questions that remain unanswered, such as the exact molecular

targets in the cell with which the ring-DIMs interact, and it is Sanderson’s hope that the novel insights uncovered by his lab will lead to real-world clinical benefits.

CYP19 AND SRD5AAlongside their work on DIM, the team is also in the middle of an NSERC-funded project aimed at elucidating the impact of certain environmental compounds on aromatase (CYP19) and steroid 5-alpha reductase (SRD5A) – two steroidogenic enzymes involved in the production of potent oestrogens and androgens, and are key players in a number of endocrine pathologies. The team hypothesises that compounds that closely resemble the endogenous androgens androstenedione and testosterone are capable of inhibiting these enzymes’ activities while also acting as AR antagonists.

Sanderson’s research programme is tackling this issue from three different angles. Firstly, work is underway to indentify the exact

structural requirements that enable chemical compounds to interfere with CYP19 and SRD5A catalytic activity, gene expression and AR signalling. Secondly, the team is elucidating the mechanisms involved in these processes through the use of in vitro cell-based assays and this work has been supported, in part, by the CBCRP in collaboration with Dr Michael Denison of the University of California, Davis. Thirdly, the lab is using bioluminescent mouse models and nanotechnology to evaluate the biological activity of these compounds in vivo.

Similar in nature to the DIM work, although at a fundamental science level, Sanderson has high hopes for the long-term clinical implications of his project. It is extremely likely that this work will produce important insights for understanding when it is appropriate to extrapolate effects seen in vitro to an in vivo context. It is also possible that the research could result in the development of novel CYP19 and SRD5A inhibitors or AR antagonists, which would have wide-ranging medical applications.

FUNDAMENTAL ANSWERSLooking to the future, Sanderson and his team plan to continue chipping away at the minute molecular mechanisms involved in endocrine disruption as a result of exposure to environmental contaminants, with an end view of elucidating how these influences result in medical benefit or harm. Sanderson is confident that his basic research will pave the way for future major medical advances and a better understanding of the risks of exposure to environmental contaminants: “My studies may be fundamental in nature, but they are all geared directly toward impacting clinical best practice or improving environmental risk assessment,” he concludes.

THE SANDERSON LAB

OBJECTIVESTo investigate the anti-androgenic and antiproliferative effects of diindolylmethane (DIM) and ring-substituted analogs (ring-DIMs) in androgen-dependent and -independent human prostate cancer cells in vitro, and in vivo using real-time imaging technology.

KEY COLLABORATORSDr Stephen Safe, Texas A&M, USADr Michael Denison, University of California, Davis, USADr Emma Guns, The Prostate Centre, CanadaDr Vladimir Titorenko, Concordia University, CanadaDr Cathy Vaillancourt, Centre - INRS-Institut Armand-Frappier, CanadaLeroy Lowe, The ‘Getting to Know Cancer’ initiative, Canada, and all the members of the international Environmental Exposures Task ForceDr Diana Montes-Grajales; Dr Jesus Olivero-Verbél, University of Cartagena, Columbia

FUNDINGNatural Science and Engineering Research Council of Canada (NSERC)

California Breast Cancer Research Program (CBCRP)

Canadian Institutes of Health Research (CIHR)

March of Dimes - Birth Defects Program

CONTACTDr Thomas SandersonAssociate Professor

Toxicologie Centre - INRS-Institut Armand-Frappier 531, Boulevard des PrairiesLaval, H7V 1B7 Canada

T +1 450 687 5010E thomas.sanderson@iaf.inrs.ca

www.iaf.inrs.ca/english/thomas-sanderson

www.linkedin.com/in/jthomassandersonwww.researchgate.net/profile/John_Sanderson6

DR THOMAS SANDERSON obtained his BSc from the Free University of Amsterdam, Netherlands, in 1989, followed by a PhD from the University of

British Columbia, Canada, in 1994. After a postdoctoral research position (1994-97) at Michigan State University’s National Food Safety and Toxicology Center, USA, Sanderson held an assistant professorship at Utrecht University, Netherlands, from 1997-2005, after which he moved to his current position at the Centre - INRS-Institut Armand-Frappier .

INTELLIGENCE

INRS-INSTITUT ARMAND-FRAPPIER RESEARCH CENTRE

Bringing together over 40 professors, 20 postdoctoral fellows and close to 140 graduate and doctoral students, the Centre boasts a strong tradition of research geared towards the improvement of health. It has an annual budget of CAD $11.2 million with $6.8 million in grants and research contracts. There are three major areas in which the Centre’s research is focused:

• Infectious diseases, immunity, cancer and epidemiology

• Microbiology and biotechnology

• Environmental toxicology and chemical pharmacology

The Centre is situated in the heart of Biotech City in the Laval Scientific and High Technology Park, in close proximity to a number of pharmaceutical and biotech companies.

‘GETTING TO KNOW CANCER’ 

This is an initiative led by Leroy Lowe of the Nova Scotia Community College, Halifax, Canada, who has formed a task force to increase awareness of the cancer risks posed by exposures to low levels of mixtures of environmental chemicals. As an active member of this task force, Dr Thomas Sanderson is hoping that increased awareness will translate into future funding in this area of environmental toxicology and cancer.

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