___

• Predictive response to therapy et al. 2009
• miR-31 downregulation miRNA E2F2
• Predictive response to therapy Rokah et al., 2012
• miR-564 downregulation miRNA E2F3, Akt2
• Predictive response to therapy Rokah et al., 2012
• miR-155 downregulation miRNA E2F2, cyclin D1,
• K-ras, PIK3R1, SOS1 to therapy Rokah et al., 2012
• ncRNA: noncoding RNA, N/A: not available. of disease. It was also documented that CD34+ leukemia stem cells are insensitive to imatinib and dasatinib, and therefore these applications would be ineffective unless directly targeting leukemic stem cells to induce apoptosis
• (Graham et al., 2002; Hu et al., 2006).
• Furthermore, the existence of CSCs is reported in
• other solid tumors. Breast cancer is the first solid tumor
• in which CSCs with the CD44+/CD24– surface marker
• was identified (Al-Hajj et al., 2003). Many CSCs have been
• identified and characterized for brain tumors, lung cancer,
• colon cancer, pancreas cancer, and prostate cancer so far
• (Singh et al., 2003; Kim et al., 2005; Ricci-Vitiani et al.,
• 2007; Li et al., 2009; Goldstein et al., 2010).
• Signaling pathways such as BMI-1, Notch, and
• Hedgehog have important roles in stemness and also
• regulate the activities of CSCs. After developing mice
• deficient in β-catenin in the hematopoietic cells, HSC
• and CSCs were isolated. Results showed a lack of the
• capacity for self-renewal, indicating the requirement of
• Wnt signaling in CSC maintenance (Zhao et al., 2007).
• The Hedgehog signaling pathway is as important as the
• Wnt signaling pathway in terms of stem cell regulation
• and embryonic formation. Suppression of Smoothened
• (Smo) decreased the triggering of CML stem cells in
• human (Zhao et al., 2009). In addition, it was shown that
• there is crosstalk among Sonic Hedgehog, Hox, and Notch
• signaling to induce the potential of CSCs (Sengupta et al., 2007).
• Since potential drugs target cancer cells instead of
• CSCs, drug resistance remains the major problem during
• treatment. In order to prevent the production of new
• cancer cells by cancer stem cells and to overcome reversal
• of resistance, recent studies have focused on targeting
• CSCs. It was agreed that imatinib and other TKIs could
• not be effective on cancer stem cells due to disease relapse
• in the long-term (Corbin et al., 2011; Perl and Carroll,
• 2011). Distinguishing cancer stem cells from normal stem
• cells is another crucial point for the success of treatment.
• It is possible to eliminate normal stem cells by targeting
• the B-lymphoid kinase gene (Blk), which acts as a tumor
• suppressor in leukemic stem cells. However, this gene
• does not show any activity in normal hematopoietic stem
• cells. Decreased levels of Blk resulted in high potency
• of leukemic stem cells, while high levels of Blk caused
• inhibition of CSCs. Suppression of Blk by targeting its
• upstream regulator Pax5 or downstream effector p27
• could be a possible target for elimination of CSCs (Zhang
• et al., 2012). Jak2/STAT5 is another potential target for
• CSCs and is related to drug resistance and CSC activity
• in leukemia cells (Jİrgensen and Holyoake, 2007; Samanta
• et al., 2011). Compared to normal stem cells, SIRT1
• (NAD+ dependent deacetylase), an inactivator of p53, is
• overexpressed in leukemic stem cells. It was reported that
• SIRT1 knockdown combined with imatinib triggered p53
• activation and apoptosis synergistically in CML stem cells
• (Li et al., 2012). It was also shown that imatinib treatment
• increased the survival rate in SIRT1 gene knockout mice.
• Therefore, SIRT1 could be a novel target for reversal of
• drug resistance in CML (Yuan et al., 2012).
• Reversal of resistance
• Drug resistance is the major problem of the clinical
• process, causing disease reoccurrence and tumor relapse.
• In recent years, there have been increasing studies to
• overcome the problem of drug resistance. Researchers have
• focused on the reversal of resistance and many techniques
• have been developed. There are various methods such
• as signaling pathway targeting, direct protein targeting,
• nanotechnology, or knockdown/knockout techniques.
• TKIs and their effects on MDR were shown as potential
• agents for reversal of drug resistance. The combination
• of imatinib and 5-bromotetrandrine has a significant
• reversal effect on the K562/A02 cell line by decreasing
• the MDR1 gene and downregulating P-gp expression
• while increasing apoptosis (Chen et al., 2010). It was also
• indicated that nilotinib reverses resistance by blocking
• ABCB1 and ABCG2 transporters (Tiwari et al., 2009). On
• the other hand, salinomycin was found to be an effective
• agent to overcome ABC transporter-mediated drug
• resistance and apoptosis resistance in leukemic stem cells
• (Fuchs et al., 2010; Riccioni et al., 2010). In vivo studies
• have also demonstrated that imatinib combined with
• vincristine significantly suppresses tumor initiation in
• multidrug-resistant CML cells in a human-nude mouse
• xenograft model (Gao et al., 2006). In another study,
• imatinib was a highly effective agent for P-glycoprotein
• mediated resistance, whereas, in imatinib-resistant cell
• lines, cepharanthine was reported as able to overcome the
• resistance of K562/MDR cells (Mukai et al., 2003).
• The Hedgehog signaling pathway prominent during
• cell proliferation was affected by suppression of the
• B4GALT1, gene which resulted in overcoming multidrug
• resistance in human K562 adriamycin-resistant cells
• (Zhou et al., 2012). The phosphatidylinositol-3-kinase/
• protein kinase B (PI3-K/Akt) signaling pathway is one
• of the important signaling pathways for cell survival. In
• human leukemia cells, LY294002, an inhibitor of PI3-K,
• reverses P-glycoprotein-mediated resistance (Zhang et al.,
• 2009). Human K562 leukemic cells are resistant to tumor
• necrosis factor-related apoptosis-inducing ligand (TRAIL)
• mediated apoptosis. It was shown that it is possible to
• reverse resistance by knocking down the DNA-PKCs/Akt
• pathway activated by TRAIL-induced apoptosis (Kim et al., 2009).
• Nanotechnology has become an important tool for
• cancer treatment and reversal of resistance. Many studies in this area have used nanoparticles. For example, as a system for targeted drug delivery, magnetic nanoparticles were used with wogonin and Fe3O4 for the reversal of MDR by downregulating MDR1 in K562 cells (Cheng et al., 2012). It was also indicated that the combination of daunorubicin and
• 5-bromotetrandrine or imatinib and 5-bromotetrandrine
• loaded onto iron oxide nanoparticles could overcome MDR
• (Chen et al., 2010; Cheng et al., 2011). Furthermore, magnetic
• nanoparticles with daunorubicin increased apoptosis and
• reversed MDR in K562-n/VCR cell vaccinated nude mice in
• in vivo studies (Chen et al., 2009). Targeting CSC-specific
• miRNAs with curcumin or epigallocatechin-3-gallate was
• reported as a potential technique for reversal of resistance
• (Wang et al., 2010).
• Conclusion and future perspectives
• Leukemia is a heavily investigated type of cancer for the
• development of new therapy strategies to cure the disease
• or increase patient quality of life. Although patients may
• respond to chemotherapy in the short term, after treatment,
• relapse can be observed. Rather than the development of
• new agents, it is better to focus on drug resistance and its
• mechanisms. A better understanding of the mechanisms
• of drug resistance could open new research areas and take
• us one step forward in cancer treatment.
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