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Introduction
Colorectal cancer is the third most common cancer worldwide (1), with nearly 1.36 million new cases diagnosed in 2012 (2). A major impediment in the success of available therapies is the recurrent adaptation of cancer cells, which evade from the tumor, and eventually reach and settle at distant sites, leading to metastases, which are often considered as the point of no return, and are associated with the worst outcome. Therefore, understanding the mechanisms that drive resistance of cancer cells bears special importance. Several such mechanisms have been studied in depth in numerous experimental setups. These include, but are not limited to: i) increased clearance of the drugs, either through increased efflux, decreased influx or increased metabolism that limit the in-cell life span of the compounds; ii) decreased metabolic conversion/activation of pro-drugs, which restricts the cytotoxic effect of the active product; iii) increased repair capacity towards cytotoxic or genotoxic damage; iv) decreased engagement of the apoptotic machinery in response to drugs (3). A rational way to understand resistance is to isolate, from cancer cells grown in vitro, cells that are resistant to therapy, and to analyze their phenotypic properties. In the context of colon cancer, as for other epithelial cancers, it has been proposed that cancer cells may originate from a small fraction of tumor initiating cells, or cancer stem cells (CSC) that are located near the bottom of the crypts (4,5). There is a set of therapeutic strategies based on usage of anticancer agents such as oxaliplatin or irinotecan, among many others, in colon cancer. Oxaliplatin, a third generation platinum derivative, is frequently used for treating advanced CRC, in association with 5-fluorouracil. This platinum analogue inhibits tumor cell growth by covalent DNA binding (6). Several studies reported that platinum agents enter the cells by passive diffusion and may be detoxified predominantly by the glutathione system (3). Docetaxel (taxotere), an analogue of taxol, inhibits cell replication upon promoting the in vitro assembly of stable microtubules and inducing microtubule-bundle formation (7). It is used for the treatment of a number of solid tumors such as breast, prostate, non-small cell lung cancer, and gastric adenocarcinoma, but it had limited activity in colon cancer patients (8). Passive diffusion is believed to be the mechanism of uptake...