Page 50 - Read Online
P. 50

Cote et al. J Cancer Metastasis Treat 2022;8:36  https://dx.doi.org/10.20517/2394-4722.2022.41  Page 7 of 11

               Table 1. Targeting ROS in cancers including malignant mesothelioma
                Source citation          Topic                                PMID
                Chen et al. [86]  (2007)   Vitamin C (ascorbate)              (17502596) (30254147)
                         [87]
                Alexander et al.   (2018)                                     (34639220)
                       [88]
                Mehdi et al.   (2021)
                       [5]
                Cunniff et al.  (2015)   Modulating PRX3 and/or FOXM1         (26011724) (33498547) (22761781)
                       [6]
                Nelson et al.  (2021)                                         (23018647)
                Newick et al. [55]  (2012)
                Cunniff et al. [56]  (2013)
                Scalcon et al. [59]  (2018)   Thioredoxin and thioredoxin reductase inhibitors  (29596885) (21215310)
                       [99]
                Zhang et al.   (2011)
                Omenn et al. [82]  (1996)   Vitamin E and Beta Carotene       (8602180) (8127329)
                              [83]
                Alpha-Tocopherol et al.   (1994)
                Gorrini et al. [17]  (2013)   Reviews                         (24287781) (33418995)
                      [65]
                Jezek et al.   (2021)
                                                                    [55]
               by TRX2 and a significant increase in mitochondrial ROS levels .
               Studies from our group identified the increased expression of FOXM1 in MM tumors and MM cell lines .
                                                                                                       [55]
               This observation led to testing the proposed FOXM1 inhibitor, TS, in preclinical models of MM. TS shows
                                                                [100]
               potent anticancer activity in a variety of tumor cell lines  and has been proposed to exert its anticancer
               activity through inhibition of FOXM1 , the proteasome [102,103]  and PRX3 activity . Our group has been
                                                [101]
                                                                                     [5,6]
               investigating the molecular mechanism and anticancer activity of TS in preclinical cell and animal models of
               MM and have deduced that PRX3 is a primary molecular target of TS [5,6,23,55,56,61]  [Figure 1]. MM cells are
               more sensitive to TS compared to normal primary and immortalized mesothelial cell lines, and TS has
               potent  in  vivo  activity  in  xenografts  of  human  MM  cells  engrafted  to  the  peritoneal  cavity  of
               immunocompromised mice. These studies have collectively shown that TS covalently crosslinks the active
               site Cys 108 and Cys 229 residues, inducing a stable covalent adduct across the dimer-dimer interface.
               Crosslinking of PRX3 increases cellular and mitochondrial ROS levels that can be inhibited by pre-
               treatment with the ROS scavenger N-acetylcysteine (NAC), indicating the redox dependency of TS
               cytotoxicity. The crosslinking of PRX3 by TS was detectable in tissue resected from mice harboring MM
               xenografts, providing evidence that the mechanism of PRX3 crosslinking by TS is preserved in vivo. Our
               recent work uncovered the specificity of TS for mitochondrial PRX3 versus the cytosolic peroxiredoxins
               PRX1 and PRX2. Structural transitions of PRX3, dependent on its oxidation status and the local pH
               environment of the mitochondrial matrix, support preferential adduction of PRX3 in MM cells. TS
               treatment of MM cells also leads to a loss in FOXM1 expression. The interplay between TS, PRX3, mROS
               and FOXM1 remains unclear as knockdown of PRX3 reduces FOXM1 levels and treatment of MM cells
               with mROS inducing agents (rotenone) leads to loss of FOXM1. Although more research is necessary to
               dissect this interplay, targeting PRX3 and FOXM1 with TS is an exciting therapeutic approach. TS is
               currently being tested in the MITOPE phase 1/2 clinical trial to evaluate activity in patients with malignant
               pleural effusion (MPE) arising from metastatic disease or M (NCT05278975).

               CONCLUSIONS
               ROS have a complicated role in the development of MM and many other cancers. Although a potent and
               cancer promoting signaling molecule, increased ROS and adaptations to oxidative stress in cancer cells,
               including MM, provide a redox vulnerability exploitable through redox-dependent therapies. Several
               preclinical and established cancer treatments exploit the increased ROS production observed in cancer by
               directly inducing oxidative stress or targeting complex cellular antioxidant networks. A secondary and
               complementary approach is targeting mitochondrial dynamics, as they are intertwined with many of the
               same redox processes. MM cell lines display both increased ROS production and altered mitochondrial
   45   46   47   48   49   50   51   52   53   54   55