Curing prostate cancer without side effects

Thus, PC accounts for about 1 in 4 newly diagnosed cancers each year among USA men, and in 2010, approximately 32,050 men are expected to die from this disease in the USA alone. This, coupled with the fact that 2.5 million cases of PC are freshly diagnosed every year in Europe, 9% of which prove fatal, makes the search for effective therapeutic strategies a matter of urgency.

Traditionally, the disease has been treated based on the premise that male steroidal hormones (androgens) are essential for the growth and progression of PC, a Nobel-prize-winning discovery by Charles Huggins and co-workers. We can think of the malignant prostatic tumor as an overgrowth of adult prostatic epithelial cells, which will be checked by reducing the levels of circulating androgens (Figure 1). One way to lower androgen levels is to use a drug that can inhibit the enzyme that produces the molecules - known as precursors - that eventually turn into androgens. The enzyme is called cytochrome P450 17?-hydroxylase,C17,20-lyase or CYP17. Ketoconazole which was first used as an antifungal compound and later found to inhibit CYP17, has been used clinically for PC treatment for nearly 30 years. However, the drug has serious side-effects such as nausea, vomiting, stomach pain, skin rash, severe hepatic disfunction, and gynecomastia. Therefore, a search for alternatives has been actively pursued for the past three decades, and abiraterone acetate, a steroidal compound and a potent CYP17 inhibitor, has already undergone Phase I and II clinical trials.

Novel steroidal androstane derivatives as potential inhibitors of CYP17 have been synthesized and evaluated at the Faculty of Pharmacy, University of Coimbra, Portugal, by Dr Vânia Moreira, under the supervision of Dr Jorge A. R. Salvador in collaboration with the Department of Pharmacology and Experimental Therapeutics at the University of Maryland, Baltimore, USA, as part of doctoral work (FCT SFRH/BD/12508/2003). The derivatives were designed based on earlier work by the research team at Baltimore, which had developed two potent inhibitors of CYP17 in which nitrogen-containing heterocyclic moieties are attached to the androstane core (Figure 1). The compounds we synthesized share this feature and some of them not only inhibited the target enzyme but also prevented several lines of PC cells from multiplying. What is more, some of these compounds specifically inhibited the multiplication of PC-3 cells, which originate when PC spreads to the bones and thus could be helpful in the management of more advanced stages of the disease. We also tested the compounds we developed on other targets related to PC, such as the structures androgens bind to in the body in order to produce their effects, and found that these structures could be blocked by some compounds at high concentrations, thus suppressing androgen activity. The multiple actions of the compounds on several targets related to PC make the compounds particularly promising and further testing of the compounds is under way.

As part of our ongoing research on cancer, our attention is now focused on a novel molecular target called proteasome. Proteasome is a major complex that can break down cellular proteins and thus affects several functions in cells including growth, the ability to repair DNA, and lifespan. By inhibiting proteasome, therefore, we can kill the tumour cells selectively leaving non-tumour cells unharmed. Also, the efficacy of several therapies commonly used in treating cancer may be improved with proteasome inhibition by a variety of mechanisms, which so far remain unexplained. Proteasome is reported to be inhibited by bortezomib, a potent anti-tumour compound approved by the Food and Drug Administration for treating blood tumors such as multiple myeloma and mantle cell lymphoma. However, although relatively well-tolerated, the compound has to be administered as an intravenous injection, and its efficacy against solid tumors remains to be demonstrated. We are currently working on synthesizing and evaluating novel proteasome inhibitors (FCT SFRH/BPD/45037/2008). This collaborative project will involve three institutions: Department of Biochemistry of the Theodor-Boveri Institute, University of Wurzburg, Germany, and Centro de Neurociências e Biologia Celular and Centro de Química of the Faculdade de Ciências e Tecnologia, both at the University of Coimbra, Portugal.