According to epidemiological data, diet rich in isothiocyanates reduces the risk of cancers, including colorectal cancer [1]. Isothiocyanates reinforce endogenous cellular mechanisms that protect normal cells against endogenous and exogenous carcinogenic factors. It takes place among others by induction of multidrug resistance-associated protein (MRP). Simultaneously, MRP’s induction in cancer cells contributes to the multidrug resistance (MDR) phenomenon [2,3]. On the other hand, isothiocyanates exhibit  cytotoxic effects on tumor cells [4].
The aim of this study was to find a compound characterized by selective action - greater cytotoxicity against tumor cells and concurrent least influence on the viability of normal cells. Because the cytotoxic effect of anticancer drugs decreases due to the MDR, for this reason we are looking for compound that will selectively induce total MRP protein activity in normal cells, and inhibit it in the tumor cells. Such double action could contribute to greater sensitization of tumor cells to anti-cancer drugs and ensure proper protection of cells against toxic effects of these drugs.
Isothiocyanates with sulfinyl group (sulforaphane and alyssin) and isothiocyanates with acetyl group (2-oxohexyl isothiocyanate, 2-oxoheptyl isothiocyanate)  were objects of this study. It has been shown that changes in the structure of isothiocyanates strongly influence their biological potency [5].
In order to investigate selective action of isothiocyanates we determined their effect on the survival and transport activity of  total MRP protein in CRL1790 normal and HT29 colon cancer cells.
Cytotoxicity of isothiocyanates was examined with MTT assay. SigmaPlot program was used to determine IC50 parameter. IC50 allows for comparison of potency of tested compounds. Selectivity index (SI , SI = IC50 normal cells/IC50 colon cells) was defined to determine selectivity of the compounds. SI > 3 shows the high selectivity of tested compound between normal and tumor cells.  Total MRP transport activity test was performed using calcein assay (Calcein AM).
It was found that isothiocyanates with acetyl group acted more cytotoxically against both cell lines than isothiocyanates with sulfinyl group. Isothiocyanates with acetyl group had higher selectivity than sulforaphane and alyssin. It was found that sulforaphane was least selective (SI=2,1). In contrast, 2-oxoheptyl isothiocyanate  had the highest selectivity (SI=4.1).It was found that 2-oxoheptyl isothiocyanate  induced transport activity of total MRP in CRL1790 normal cells, and had no effect on the activity in HT29 cancer cells.
Studies have shown that 2-oxoheptyl isothiocyanate  has high selectivity. It also induces the endogenous protective mechanisms in normal cells. Such action of 2-oxoheptyl isothiocyanate  could be used to increase the effectiveness of anticancer drugs and reduce side-effects of therapy.

References:

1.Chung FL, Conaway CC, Rao CV et al (2000) Carcinogenesis 21:2287-2291.
2.Shen G, Kong A-N (2009) Biopharm Drug Dispos 30:345-355.
3.Sharom FJ(2008) Pharmacogenomics 9:105-127.
4. ZhangY, Tang L,Gonzalez V (2003) Mol Cancer 2:1045-5102
5.Mazur P, Magdziarz T, Bak A, et al (2010) J Mol Model 16:1205-1212

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