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Ibrahim et al                                                                                                                                                                                        ALDHs and prostate cancer

           Early studies first demonstrated a chemo-resistant   to the multidrug resistance (MDR) and enhanced
           role for ALDHs in a CPA resistant L1210 leukaemia   tumourigenicity of CSCs [214] . Within the proposed
           cell line [206] . This study showed that high levels of   hypoxic CSC niche, the cells are surrounded
           ALDH activity were found in L1210 cells and that   by an acidic microenvironment that activates a
           treatment with disulfiram (ALDH inhibitor) reversed   subset of metastasis promoting proteases such as
           the resistance phenotype of the cells to CPA. A    MMPs and cathepsins   [215] . As a consequence of
           subsequent study confirmed the role of ALDH-       poor angiogenesis and the inaccessible location,
           mediated CPA resistance in medulloblastoma   [207] .   hypoxic cells are exposed to insufficient drug
           Similar studies demonstrated that high ALDH activity   concentrations, which promote the survival of a drug-
           indicates CPA resistance in cancer and CSCs  [208] .   resistant sub-population of cells. The lower oxygen
           Accordingly, inhibition of ALDH activity can in    tension increases resistance to radiotherapy and as
           principle serve to sensitise CSCs to drugs such as   discussed above, also enriches CSC niche within
           CPA [209] . More specifically, ALDH1A1 and ALDH3A1   the TME. Hypoxia-activated prodrugs (HAPs) have
           were both shown to inactivate CPA analogues [210,211] .   been investigated for several decades and have
                                                              shown considerable promise in combination with
           The sphere forming cells (a common property of     chemotherapy or radiotherapy, but no HAPs have
           CSCs), from the sarcoma cell line MG63 were        yet been approved for clinical use. Unravelling the
           significantly insensitive to doxorubicin and cisplatin   PCa microenvironment is likely to offer new insight
           treatment compared with monolayer adherent         and opportunities to molecularly stratify patients for
           counterparts.  The sarcosphere cells with high     treatment, based on their tumours’ hypoxic signature,
           ALDH1 activity were proposed as candidate sarcoma   including analysis of enzymes with oxidase and/
           SCs, in which efficient drug detoxification is likely to   or reductase functionality. Prostate tumours are
           have contributed to generation of a chemo-resistant   considerably hypoxic as discussed in this thematic
           CSC  phenotype   [191] .  Furthermore,  high ALDH   issue [216]  and enzymes such as ALDHs are likely to
           expression in CSCs has shown chemo-resistance      be expressed differentially within the TME due to
           in both breast CSCs  [190,212]  and head and neck   different pressures including hypoxic stress and types
           squamous cell carcinoma (HNSCC) SCs   [213] , where   of cells such as MDR and CSCs.
           ALDH expression was associated with high Snail
           expression, a marker of EMT. Knockdown of Snail    The limited sensitivity of hypoxic tumours to
           expression significantly decreased the expression   radiotherapy may in part be related to CSCs residing
           of ALDH1 whilst blocking the tumorigenic abilities   in the hypoxic niche. Primary human PCa samples
           of CD44+ CD24- ALDH1+ cells   [213] . Although many   express both elevated levels of ALDH1A1+ and
           chemotherapeutic drugs are less effective in ALDH-  hypoxia inducible factor 1 alpha (HIF-1α), which
           expressing cancer cells, the underlying mechanisms   have been linked to radioresistance [217,218] . A recent
           are poorly understood. None of the drugs contain   study [219]  demonstrated that irradiation enriched
           aldehyde functional groups that are direct substrates   the CSC population of DU145 and PC-3 cells. The
           for biochemical reactions with ALDHs, but esterase   irradiated cells were shown to possess elevated
           activity has been shown for some of these enzymes,   ALDH functional activity as well as DNA damage
           which potentially provides an ALDH mediated        response activity, and in vivo the irradiated ALDH+
           resistance mechanism for drugs such as the         cells were shown to maintain their tumorigenic
           taxanes. Phase 1 metabolism resulting in short lived   properties, suggesting these might be radioresistant
           aldehydes as illustrated for CPA are direct substrates   in vivo. Furthermore, in primary human prostate
           for ALDH  detoxification,  providing  a  potential   tumours, IHC analysis revealed co-localisation of
           resistance mechanism in ALDH+ expression cells     ALDH1A1 and HIF-1α expression, implying that
           including CSC population within the TME [Figure 2].   a subset of ALDH+ cells resides in the hypoxic
           Drug resistance can be reversed by co-treatment    niche and emphasising the need to target these to
           with an ALDH inhibitor such as DEAB. For example,   effectively eradicate heterogeneous prostate tumours.
           doxorubicin, paclitaxel and radiotherapy resistance in
           breast cancer cell lines has been reversed following   In other tumours, for example radiation resistant
           treatment with DEAB or RA [190] .                  mesenchymal glioma, the SCs (MGSCs) possess
                                                              elevated glycolytic activity and ALDH activity, in
                                                              contrast to benign proneural SCs. Expression of
           ALDH, HYPOXIA AND TME                              ALDH1A3 was increased in clinical high-grade
                                                              glioma compared with low-grade glioma or normal
           Hypoxia is not only a major feature of the tumour   brain tissue [220] . Encouragingly, although the MGSCs
           microenvironment but is also a potential contributor   were very aggressive in vitro and in vivo, the pan-
             8                                                                      Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018
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