Bioreductive DNA alkylating agents rely on reductive activation by reductase enzymes to be effective in the human body. PR-104A is an experimental anticancer drug and the first hypoxia-activated nitrogen mustard alkylating agent to enter clinical trials. Besides being activated under hypoxic conditions, the aldo-keto reductase 1C3 (AKR1C3) was shown to be responsible for PR-104A activation under aerobic conditions. By increasing the amount and the activity of AKR1C3 in cancer cells, the function of PR-104A may be promoted, possibly leading to improved therapy outcomes. Sulforaphane (SF), a bioactive food component derived from cruciferous vegetables, can modulate drug metabolizing enzymes like AKR1C3. We hypothesized that if SF promoted AKR1C3 enzyme levels as well as activities in cancer cells, then this should translate to enhanced PR-104A cytotoxicity. In this study a combination of molecular approaches such as quantitative proteomic techniques and activity probes, were used to observe an up to 7-fold increase in AKR1C3 levels and 2.3-fold increase in activity in SF-treated colon cancer cells. Furthermore, this increase appeared to contribute to increasing the cytotoxicity of PR-104A. To test whether this response was not also evident for healthy colon epithelial cells, where promoting toxicity should be avoided, we compared the combined response of SF and PR-104A in different colon cancer cell lines as well as immortalized human colonic epithelial cells that model the responses of healthy tissue. Results that support a mechanism explaining how SF can modulate drug metabolizing enzymes and enhance the cytotoxicity of bioreductive anticancer drugs selectively in cancer cells over non-cancerous cells will be presented.

Impact of sulforaphane on cytotoxicity of bioreductive anticancer drug PR-104A in human colon cells

248th National Meeting (2014)

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