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Review

Colon cancer: Cancer stem cells markers, drug resistance and treatment Q1 Zuzana a b

Kozovska a,1,*, Veronika Gabrisova b,1, Lucia Kucerova a

Department of Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 83391 Bratislava, Slovakia Department of Cellular and Molecular Biology of Drugs, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 83232 Bratislava, Slovakia

A R T I C L E I N F O

A B S T R A C T

Article history: Received 12 August 2014 Accepted 15 October 2014

Malignant tumours consist of heterogeneous populations of tumour cells. Cancer stem cells (CSC) represent a population of cells within a tumour with highly tumorigenic and chemoresistant properties. These cells may be identified by the expression of CSC markers. There are several key stem cells markers specified for colon cancer: CD133, CD44, ALDH1, ALCAM. These days, a major obstacle to effective cancer management is development of a multidrug resistance (MDR). The principal mechanism responsible for development of MDR phenotype is the over-expression of ABC transporters. Tumours and relapsing tumours after therapy are drived by subpopulations of tumour cells with aggressive phenotype resistant to chemotherapeutics. These cells are called CSC or tumour-initiating cells (TIC). Here we outline recent information about MDR of colon cancer and CSC markers. We have focused on novel therapeutic strategies which have been developed to prevent or overcome MDR. One such strategy is a combination of chemotherapy and modulators of MDR pumps or chemotherapy and monoclonal antibodies against vascular endothelial growth factor VEGF. Colon cancer is characterized by the presence of colon CSC expressing specific stem cell markers. The divergent presence of these markers can help to adjust personalized therapy. The review provides a detailed overview of resistance of colon cancer cells and discusses how the presence of CSC markers can influence therapy and prognosis of patients. ß 2014 Published by Elsevier Masson SAS.

Keywords: Colon cancer Cancer stem cells markers Multidrug resistance Aldehyd dehydrogenase ALDH1

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1. Introduction

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Cancer is a genetic disease characterized by uncontrolled cell growth and the ability to invade other parts of the body by forming metastases. Malignant tumours consist of heterogeneous populations of cancer cells. CSC form a subpopulation of cells within a tumour which display the capacity of self-renewal and differentiation. These cells, also described as TIC, are presumed to promote growth and metastases of tumours [1]. There were 14.1 million new cancer cases, 8.2 million cancer deaths and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012 worldwide (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). GLOBOCAN 2012 (IARC), Section of Cancer Information (16/6/2014). The chemotherapy failure is attributed to the development of a MDR. The MDR phenotype accounts for unsatisfactory low response rate of solid tumours to chemotherapy in patients treated chronically with antineoplastic agents. This clinical

* Corresponding author. Tel.: +421 2 59327418; fax: +421 2 59327250. E-mail address: [email protected] (Z. Kozovska). 1 These authors contributed equally to this work.

phenomenon results from the ability of cancer cells to become simultaneously resistant to many structurally dissimilar and functionally divergent drugs used in anticancer therapy [2]. The over-expression of ABC transporters represents the principal mechanism by which cancer cells develop MDR. Increased drug efflux mediated by ABC transporters leads to decreased intracellular drug accumulation, hence to the decreased bioavailability. Combination therapy using more than one medication at the same time may be used to overcome MDR [3].

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2. Progression of cancer

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Several types of pre-malignant lesions, such as dysplasia and hyperplasia, can be detected in diverse organs prior to the appearance of fully malignant invasive tumours. An early stage of cancer characterised by the absence of invasion of tumour cells into the surrounding tissue, before penetration through the basement membrane, is called carcinoma in situ. Accumulation of genetic alterations occurs in one (or a few) of the pre-malignant cells, and the cells convert into malignant ones of clonal origin and produce a primary tumour. After the initial transformation and growth of cells, neoangiogenesis arises. At the early stage of

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http://dx.doi.org/10.1016/j.biopha.2014.10.019 0753-3322/ß 2014 Published by Elsevier Masson SAS.

Please cite this article in press as: Kozovska Z, et al. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.10.019

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primary tumour expansion, the cells are not invasive and metastatic. Invasiveness and metastatic ability appears as a result of further accumulation of genetic alterations in the cells. Diagnosis and treatment of cancer occurs generally late in the course of disease, in some types of cancer perhaps more than 10 years prior to the acquisition of the invasive phenotype [4]. At this stage, a high proportion of patients have obvious or occult metastases.

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3. Metastases

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Despite the significant improvements in diagnosis, surgical techniques, specificity of cancer treatment, patient care and adjuvant therapies, yet there is no cancer treatment that is able to cure majority of the patients with metastatic disease. The major obstacles to effective treatment include the biologic heterogeneity of tumour cells, the specific organ microenvironment, which influences the biologic behaviour of metastatic cells, including their response to systemic therapy and the development of drug resistance phenotype in metastatic cancer cells [5–7]. New and very promising approach for treatment of the metastases is a gene therapy using genetically modified mesenchymal stromal cells (MSC), which are able to convert a nontoxic prodrug to a highly toxic chemotherapeutic at the site of the tumour (so-called genedirected enzyme/prodrug therapy; suicide gene therapy) [8–12].

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4. Cancer stem cell theory

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Cancer is known to result from the accumulation of multiple genetic mutations in a single target cell, sometimes over a period of many years [13]. Although monoclonal in origin, most tumours are recognised as a morphologically heterogeneous population of cancer cells [14]. This tumour heterogeneity can be explained by variations in tumour microenvironment and genomic instability [15–17]. CSC theory brings additional explanation, stating that intratumour heterogeneity can result from a functional diversity among cells in different states of differentiation [18]. Cancer cells within tumours may display different phenotypes, somewhat reminiscent of the normal tissue from which they originate, and have varying proliferation potential [19]. The CSC theory proposes that tumours have a cellular hierarchy that is a caricature of their normal tissue counterpart because they reflect the pluripotency of the originally transformed cell [20]. According to this hypothesis, only a subpopulation of cells within a cancer, made up of so-called CSC or TIC, have the exclusive capacity to regenerate a tumour and sustain its growth. Purified CSC are known to be potently tumourigenic [21]. They are able to regenerate the tumour from which they were derived when a limited number of cells (sometimes as few as 102 cells) are injected into an orthotopic in vivo microenvironment [20,22]. The other cancer cells have only a limited capacity to replicate and thus contribute to the tumour bulk but not to tumour maintenance [20]. CSC demonstrate some properties of normal stem cells, such as self-renewing abilities and differentiation capacity. Self-renewal is a unique replication process that allows stem cells to divide and give rise to either one or two stem cells [23]. In normal tissues, the expansion of the stem cell pool is restricted to prevent uncontrolled growth [24], whereas extensive and indefinite selfrenewal is observed in CSC. CSC either originate from normal cells that became malignant or committed cells that acquired selfrenewal capacity. Asymmetric division enables CSC to self-renew, thus forming another CSC, and a more committed progenitor cell. Subsequently, progenitor cell divides and differentiates to form a malignant progeny [25]. CSC are able to self-renew in vivo after serial transplantation in secondary and tertiary recipients when

phenotypically identical and heterogeneous tumour is observed [21]. Differentiation is the second function of a stem cell and involves the potential to form tissue-specific specialized cells. Tumours arising from CSC demonstrate differentiation capacity in vivo by creating a phenocopy of the original human tumour.

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4.1. Colorectal CSC

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There is now accumulating evidence for the existence of colorectal CSC in human colorectal cancer (CRC) [18,26–29]. Using the CD133 surface marker in two separate studies [26,27], highly tumourigenic and self-renewing colorectal CSC population in human colon cancers have been successfully enriched and CD133+ human cancer cells were found capable of inducing tumour formation while CD133 cancer cells failed to do so [27]. The CD133+ cells produced passageable sphere-forming cells that remained undifferentiated for more than one year and were able to initiates in vivo tumours that were phenotypically similar to the original tumour [27]. In a renal capsule xenograft model, CD133+ cells could generate tumours, but CD133 cells were unable to do so [26]. Moreover, CD133high populations displayed a much more aggressive phenotype than CD133/low cells, in terms of metastases, implicating CD133 as a marker of increased tumourigenicity [30]. In addition, CD133+ single cell clinical tumour-derived cultures were shown to possess multilineage differentiation potential and were capable of tumour initiation in vivo [31]. CD133+ overexpressing tumours were more resistant to 5FU-based chemotherapy and CD133 expression was associated with poor prognosis [32]. RNA interference approach showed that knockdown of CD133 had no effect on in vitro clonogenicity or in vivo xenograft tumour formation, demonstrating that CD133 is rather a passive marker of colorectal CSC [33]. Another subset of tumourigenic human colon cancer cells was identified based on ESAhighCD44+ CD166+Lineage colon cancer phenotype [18]. Knockdown of CD44 (hyaluronate receptor, P-gp 1) resulted in limited colony formation and dramatically reduced tumour formation in xenografts, strongly implying a functional role of CD44 in CRC tumourigenesis [33]. Aldehyde dehydrogenase 1 (ALDH1) is a promising new marker for identification of colorectal CSC. ALDH was found to be a specific marker for identification, isolation and tracking of malignant human colonic CSC and for quantifying the number of CSC over the course of CRC development [28]. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (ALDEFLUORassay) and implantation of these cells in NOD-SCID mice:

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 generated xenograft tumours (Aldefluor cells did not);  generated them after implanting as few as 25 cells, and;  generated them dose dependently [28].

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ALDH is an intracellular enzyme that oxidizes aldehydes, possess a detoxifying role, converts retinol to retinoic acid [34], mediates control over differentiation pathways [35], plays an important role in self-protection of normal stem cells [36] and confers resistance to alkylating agents. ALDH is now widely used as a marker for identification and isolation of various types of normal stem cells and CSC. ALDH can confer resistance to selected anticancer agents by metabolic inactivation [37] and it is speculated to be a cause of relapse in cancer patients [38– 40]. ALDH1A1 is one of the 19 ALDH isoforms expressed in humans. In many cancers, high ALDH1 expression is associated with metastases development and correlates with poor clinical outcome [41,42]. Recent evidence suggests that ALDH activity may protect against cell death caused by reactive oxygen species (ROS) [43]. ALDH activity can be inhibited pharmacologically by

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Please cite this article in press as: Kozovska Z, et al. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.10.019

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4-diethylaminobenzaldehyde (DEAB) (Fig. 1). Because chemotherapy is known to induce oxidative stress [44], it is possible that inhibition of ALDH activity using DEAB may sensitize ALDHhi CSC to therapy through enhanced exposure to ROS and induction of apoptosis [41]. We were able to increase susceptibility of colorectal cancer cells (HT-29) to chemotherapy after incubation with DEAB in our preliminary study. We would like to confirm this observation by molecular inhibition of ALDH with specific siRNA (small interfering RNA) towards ALDH1 isoforms in our research.

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4.2. Clinical implications of the CSC model

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Nowadays, clinical treatment regimens operate under the assumption that all cancer cells have equal malignant potential [20]. However, since CSC are potentially more resistant to antineoplastic therapy and probably cause disease recurrence and/or metastases [45], therapeutic approaches that do not eradicate CSC are likely to fail. They might kill the bulk tumour population and induce temporary regression of gross tumour lesions but fail to prevent disease relapse and metastatic dissemination. Even though these drugs help to maintain longterm remissions, they are not curative. It is, therefore, necessary to design new and more effective antitumour treatments that would specifically target the CSC subpopulation [46]. Targeted therapies, selective to CSC and non-toxic to normal stem cells, hold a great promise for the effective and curative therapy of many human cancers. Antitumour treatments designed and selected for broad cytotoxic activity may kill the majority of cancer cells within a specific tumour tissue and induce dramatic, even complete regression of large tumor masses; however, if any of the CSCs are spared, tumour tissues can be regenerated and cause disease relapse. In contrast, antitumour treatments specifically designed to target CSCs, although theoretically unable to cause rapid shrinkage of tumour lesions, might nonetheless achieve long-term disease eradication by exhausting the self-renewal and growth potential of cancer tissues [47].

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5. Treatment

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Management of CRC relies primarily on resection of the bowel with the adjacent lymph nodes. The need for neoadjuvant or adjuvant chemotherapy, with or without concurrent irradiation, depends on tumour location and a stage of the disease. Early stages of CRC are treated primarily by surgery-laparoscopic colectomy, if possible. A combination of surgical and other therapeutic modalities is indicated if regional or distant metastases are discovered at the time of diagnosis. Adjuvant treatment for CRC is indicated for curative-intent resections of stage IV disease and for stage III disease [48]. The utility of adjuvant therapy in stage II disease remains unclear and controversial [49]. High-risk patients might be considered for such treatment. On the other hand, patients with poorer prognosis may benefit more from the palliative care instead of chemotherapy. After decades of 5-FUbased treatment, the arrival of new, effective agents has significantly changed the way this cancer is treated. Although 5FU remains the backbone of most regimens, the new agents have become an important part of a front-line treatment providing

Fig. 1. DEAB structure.

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improvements for patients in both response and survival. Synergic or additive action and decreased toxicity and side effects of drugs represent the major benefits of combination treatment.

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5.1. 5-fluorouracil (5-FU)

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Antimetabolite 5-FU, used in the treatment of a range of cancers including CRC, acts by incorporation into DNA and RNA and thus inhibiting nucleotide biosynthesis. 5-FU is a prodrug that enters the cells using the same facilitated transport system as uracil [50]. It is intracellularly converted into three active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP).

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5.1.1. Anticancer agents used for modulation of 5-FU action 5.1.1.1. Increased TS binding activity of 5-FdUMP by leucovorin. Leucovorin (calcium folinate) increases the level of reduced folate (CH2THF; N5,N-10-methylenetetrahydrofolate), which enables 5fluorodeoxyuridine monophosphate (5-FdUMP) to bind to TS and to form stable tertiary complex resulting in increased in vitro [51,52] and in vivo [53,54] toxicity of 5-FU.

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5.1.1.2. Decreased 5-FU degradation by capecitabine. Capecitabine is an oral fluoropyrimidine prodrug that is converted to 50 -deoxy5-fluorouridine (5´DFUR) in the liver. 5´DFUR is then converted to 5FU by thymidine phosphorylase (TP) and/or uridine phosphorylase (UP) ([55,56] at the site of the tumour. Capecitabine is used to avoid dihydropyrimidine dehydrogenase (DPD)-mediated 5-FU degradation in the liver.

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5.1.1.3. Increased 5-FU activation by methotrexate. Methotrexate is an antifolate inhibitor of dihydrofolate reductase. Inhibition of purine biosynthesis by MTX increases the levels of phosphoribosyl pyrophosphate (PRPP), the cofactor of 5-FU conversion to fluorouridine monophosphate (FUMP) by orotate phosphoribosyl transferase (OPRT). The increased PRPP levels induced by MTX promote conversion of 5-FU to FUMP [57].

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5.1.1.4. Irinotecan. Camptothecin derivate, irinotecane is a prodrug whose active metabolite is a potent inhibitor of the nuclear enzyme topoisomerase I, which facilitates the uncoiling of DNA during replication [58].

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5.1.1.5. Oxaliplatin. Oxaliplatin is a platinum compound that forms cross-linking DNA adducts, thereby blocking DNA replication and transcription [59].

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5.1.2. Monoclonal antibodies used in colorectal cancer treatment 5.1.2.1. Bevacizumab. Bevacizumab is a humanized monoclonal antibody that inhibits blood-vessel formation by binding to the vascular endothelial growth factor-A (VEGF-A) [60]. It was the first anti-angiogenic drug approved for metastatic colon cancer. It prevents the binding of VEGF-A to the VEGFR and, consequently, inhibits angiogenesis, tumour growth and metastatic development [3].

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5.1.2.2. Ziv-aflibercept. Ziv-aflibercept is a recombinant fusion protein, which acts as a soluble receptor that binds to VEGF-A, VEGF-B and PlGF (phosphatidylinositol-glycan biosynthesis class F protein) and inhibits them, resulting in a decreased neovascularization and a decreased vascular permeability [3].

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5.1.2.3. Cetuximab. Cetuximab is a chimeric (human/mouse) monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor (EGFR) and blocks ligand-induced receptor signalling [60]. These anti-EGFR

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Please cite this article in press as: Kozovska Z, et al. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.10.019

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therapies have found their place in the treatment of stage IV colon cancer [3].

 induction of mechanisms that repair DNA damage [74];  alterations in the cell cycle and checkpoints [71].

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5.1.2.4. Panitumumab. Panitumumab is a fully human monoclonal antibody to EGFR, with similar activity to cetuximab [60].

6.1. Overview of ABC transporters

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5.1.2.5. Regorafenib. It is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR) [3].

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5.2. Cisplatin (CisPt)

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A platinum-based compound, cisplatin ( cis-diamminedichloroplatinum(II)) displays clinical activity against a wide variety of solid tumours, including colorectal carcinoma and malignant melanoma. The primary cellular target for cisplatin is DNA [61]. Its cytotoxic mode of action is based on DNA adduct formation, which affects many DNA-dependent cellular functions, including inhibition of replication and transcription, cell cycle arrest, and DNA damage leading to cell death and apoptosis [62–65]. The cytotoxic effect is ascribed to interaction with nucleophilic N7-sites of purine bases in DNA to form DNA–protein, DNA–DNA interstrand, but mainly intrastrand cross-links [66]. Damage recognition proteins (DRPs) of the mismatch repair (MMR) complex bind to physical distortions in the DNA and initiate the sequence of events extending from the formation of DNA adducts to the completion of the apoptosis [67]. Cisplatin resistant cells exhibit a variety of mechanisms of resistance, which arise from intracellular changes that either prevent cisplatin from interacting with DNA, interfere with DNA damage signals from activating the apoptotic machinery, or both [67]. Reduction of the extent of DNA damage increases cisplatin resistance. Reduced intracellular accumulation of the drug is a significant mechanism of resistance. Cisplatin resistant cells were shown to have a pleiotropic defect resulting in reduced plasma membrane receptors and transporters and reduced endocytosis [68] and passive drug diffusion [69], with no evidence for an energy-dependent efflux pump for cisplatin [70,71]. Another significant factor in cisplatin resistance is the increased inactivation by conjugation reaction between cisplatin and thiol-containing molecules (e.g.: GSH). Increased DNA damage repair, which attenuates the apoptotic process, is also responsible for the development of resistance.

Forty-eight ABC transporters identified in the human genome are grouped into seven subfamilies (ABCA – ABCG), based on phylogenetic analysis – similarity in the gene structure (half versus full transporters), order of the domains, and sequence homology in the nucleotide-binding domains (NBDs) and transmembrane domains (TMDs) [75]. Several ABC transporters have been found to be overexpressed in MDR cell lines. The three major proteins involved in cancer MDR are MDR1 (P-gp, ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP, MXR). Numerous studies have found a very good correlation between ABC transporters´ expression levels and poor prognosis and response to chemotherapy [76,77]. In our work, we were able to show functional relationship between resistance to 5-FU based therapy and ABCC11 expression [8].

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6.2. Overcoming MDR with inhibitors

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6. Multidrug resistance (MDR)

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Simultaneous resistance of tumour cells to the cytostatic or cytotoxic actions of multiple structurally unrelated drugs that do not have a common mechanism of action, a phenomenon that is known as MDR [71], might explain why treatment regimens that combine multiple agents with different targets are not more effective [72]. MDR cancer cells are endowed with multiple mechanisms for survival, which can result from:

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Due to the promiscuity of the ABC-transporters, a large number of high affinity substrates, which increase the cytotoxic action of MDR-related anticancer drugs by preventing their efflux from the target cells, have been found. The first generation of P-gp inhibitors (modulators) were drugs already in use for treatment of other medical conditions. It included compounds of diverse structure and function such as calcium channel blockers (verapamil), immunosuppressants (cyclosporin A), antibiotics (erythromycin), antimalarials (quinine) or anti-steroids (tamoxifen) [78]. Since these were not specifically developed for inhibiting MDR, they suffered from the dual problems of high toxicity and low efficacy at tolerable doses. Second-generation inhibitors, such as valspodar, biricodar and dexniguldipine, were synthesized around first-generation pharmacophores to increase the affinity to P-gp while reducing doselimiting toxicities. Nevertheless, reduced clearance of the anticancer drug led to increased toxicity in cases where both the treatment drug and the modulator were substrates for cytochrome P450 3A. Third-generation inhibitors, such as zosuquidar, tariquidar, elacridar and ontogen, were specifically designed to have high affinity to P-gp and low pharmacokinetic interactions [79]. It was thought that the targeted agents would be so specific that resistance would not develop. The disappointing fact is that most of these therapies improve progression-free survival but still fail to induce cures. The main goal of these modulators is to maximize therapeutic outcome by synergic or additive action without increasing cytotoxicity. The drugs used in combination should act by different mechanisms, have some efficacy by themselves, have different toxicity profiles and different mechanisms of resistance development. Another very promising strategy is the development of the drug delivery system based on liposomes to enhance drug delivery to tumour cells and to reduce plasma protein binding [80]. Novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action in cancer treatment was described [81]. Gene therapy can be used in combination with conventional chemotherapy for primary tumours and also for treatment of metastases. Development of therapies targeting CSC features holds hope for improvement of survival of cancer patients, especially patients with metastatic disease or with aggressive tumours, like glioblastoma, where in addition disseminated tumour cells in brain

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limited drug uptake; enhanced drug efflux; affected membrane lipids (e.g. ceramides) [73]; increased drug metabolism; altered drug targets; detoxification by compartmentalization; blocked programmed cell death (apoptosis);

Please cite this article in press as: Kozovska Z, et al. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother (2014), http://dx.doi.org/10.1016/j.biopha.2014.10.019

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tissue have to be attacked. Prodrug cancer gene therapy driven by engineered MSCs might be one out of several treatment modalities fulfilling these requirements [82]. It remains to be evaluated if this type of treatment can target cells with CSC properties.

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7. Conclusions

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We summarized our knowledge about current approaches to colon cancer treatment, colon CSCs and their drug resistance. Only precise identification of colon CSC and their properties can help to design effective anticancer therapy. Efficient cancer therapy which can target CSCs together with conventional chemotherapy should be applied at the same time. This strategy together with the gene therapy using genetically modified MSC, which are able to convert nontoxic prodrug to highly toxic chemotherapeutic at the site of the tumour (so-called gene-directed enzyme/prodrug therapy; suicide gene therapy), seems to be the anticancer therapy of the near future. Combinations of traditional, targeted and stem celldirected gene therapy could significantly advance the treatment of cancer [8–11,82]. There is experimental evidence that the CSC marker expression is linked to increased drug resistance [83]. Our data confirmed the same phenomenon in thyroid cancer cells linking CD133+ marker and their resistance to 5-FU [84]. It remains to be further examined whether decreased expression of CSC markers also leads to decreased expression of MDR efflux pumps and at the same time increases sensitivity of the tumour to chemotherapy.

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Disclosure of interest

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The authors declare that they have no conflicts of interest concerning this article.

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Acknowledgements

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We thank Dr. M. Cihova for reading the manuscript. The studies and experiments mentioned in this study were performed with the Q2 kind support provided by the Slovak Research and Development Agency under the contract No. APVV-0230-11 and APVV-0052-12; Slovak Cancer Research Foundation; VEGA grants No. 2/0171/13 and 2/0130/13. References [1] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [2] Marin JJ, Monte MJ, Blazquez AG, Macias RI, Serrano MA, Briz O. The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy. Acta Pharmacol Sin 2014;35:1–10. [3] Recondo GJ, Diaz-Canton E, de la Vega M, Greco M, Recondo GS, Valsecchi ME. Advances and new perspectives in the treatment of metastatic colon cancer. World J Gastrointest Oncol 2014;6:211–24. [4] Hong WK, Research AAfC, Hait W. Holland Frei Cancer Medicine Eight. People’s Medical Publishing House; 2010. [5] Dutour A, Leclers D, Monteil J, Paraf F, Charissoux JL, Rousseau R, et al. Noninvasive imaging correlates with histological and molecular characteristics of an osteosarcoma model: application for early detection and follow-up of MDR phenotype. Anticancer Res 2007;27:4171–8. [6] Langley RR, Fidler IJ. The biology of brain metastasis. Clin Chem 2013;59: 180–9. [7] La Porta CA. Drug resistance in melanoma: new perspectives. Curr Med Chem 2007;14:387–91. [8] Matuskova M, Baranovicova L, Kozovska Z, Durinikova E, Pastorakova A, Hunakova L, et al. Intrinsic properties of tumour cells have a key impact on the bystander effect mediated by genetically engineered mesenchymal stromal cells. J Gene Med 2012;14:776–87. [9] Altanerova V, Cihova M, Babic M, Rychly B, Ondicova K, Mravec B, et al. Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase: uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma. Int J Cancer 2012;130:2455–63.

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