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Page 6 of 11 Cote et al. J Cancer Metastasis Treat 2022;8:36 https://dx.doi.org/10.20517/2394-4722.2022.41

Mdivi-1, which inhibits Drp1, was most effective on cell lines with a high lacunarity. This study did not find
any correlation with their mitochondrial metabolism measurements. Although the use of treatments like
metformin is largely unproven, this suggests that mitochondrial dynamics may be a promising indicator of
[77]
the effectiveness of cancer treatments . These results suggest that mitochondrial dynamics are a useful
target for MM treatment, as well as for other tumors characterized by high mitochondrial oxidant
production.

STRATEGIES IN MODULATING MITOCHONDRIA AND REDOX SYSTEMS FOR
THERAPEUTIC INTERVENTION
Several studies recognize the difficulty in treating cancer by downregulating ROS production for the same
reasons that they are controversial in the role of cancer development. Suppressing ROS with general
antioxidants, such as β-carotene and vitamin A, was found to enhance tumor growth [82,83] . Several other
studies have criticized the commercial use of antioxidants as a means of cancer prevention. There have been
few population-based studies supporting their use . Inducing oxidative stress by selectively increasing
[17]
cellular ROS or specifically targeting key antioxidant enzymes seems to be a more viable option [Table 1].
One approach is by directly increasing ROS levels within the cell. Many well-known cancer treatments, such
[17]
as chemotherapy and radiation, already work by inducing oxidative stress . However, caution must be
exercised as inducing ROS in cells nonspecifically may induce chemoresistance [84,85] . Additional studies have
shown that some ROS-inducing agents may be able to sensitize cancer cells to treatments like radiation
[86]
therapy. One, in particular, is vitamin C (ascorbate) which acts as a pro-oxidant at higher doses and has
been shown to enhance sensitivity to radiation therapy in pancreatic cancer [87,88] . Other studies have shown
that depletion of arginine, a critical amino acid in the biosynthesis of proteins, nitric oxide, and polyamine
is an actionable approach for therapeutic intervention in argininosuccinate synthase I (ASSI) - negative
tumors, including MM [89,90] . Depletion of arginine leads to mitochondrial dysfunction and increased ROS
levels [91,92] . Pegargiminase (ADI-PEG 20; ADI) acts to degrade arginine and shows potent activity in ASS1
deficient MM tumors . Given the potent effects on mitochondrial activity, including increased oxygen
[93]
consumption and ROS levels following arginine depletion, or treatment with ADI-PEG 20, it will be
interesting to determine the redox-dependent activity of this approach in the therapeutic response
observed [92,94] .

A more specific approach to increasing ROS is by targeting antioxidant pathways. As many antioxidant
systems are upregulated in cancer cells, they have been identified as important targets for treatment that
selectively targets cancer. Thioredoxin (TRX) pathway inhibitors are an important target, as it is suggested
that overexpression of TRX leads to chemoresistance to pro-oxidant therapies . For example, cis-
[59]
diamminedichloroplatinum (II) (CDDP, cisplatin) is one of the few chemotherapeutic agents approved
[45]
[95]
for use in MM treatment , and its cytotoxicity is partly attributed to its effects on TRX activity. Studies
showed that cisplatin cytotoxicity was strongly correlated with thioredoxin reductase (TR) inhibition. This
study also showed that an increase in TR expression correlated with cisplatin resistance . Although
[96]
cisplatin activity is attributed to DNA damage, most of the intracellular platinum content reacts with GSH,
forming a bis-(glutathione)-platinum (GS-Pt) complex , which, notably, also demonstrated inhibitory
[97]
effects on TR .
[98]
Triphenylmethanes, like brilliant green and gentian violet (GV), appear to act by inhibiting the
mitochondrial thioredoxin isoform(Trx2) . GV was shown to have potent cytotoxic activity against MM
[99]
cells in culture and a xenograft model of MM . These studies corroborated initial studies that GV was a
[5]
potent TRX2 inhibitor as loss of TRX2 expression correlated with cytotoxicity . Additionally, treatment of
[99]
cells with GV led to significant increases in disulfide-bonded dimers of PRX3, the molecular species reduced