Title:Cancer Pro-oxidant Therapy Through Copper Redox Cycling: Repurposing Disulfiram and Tetrathiomolybdate
Volume: 26
Issue: 35
Author(s): Manuel Rieber*
Affiliation:
- IVIC, Cancer Cell Biology Laboratory, CMBC, Caracas 1020A,Venezuela
Keywords:
Cu chelation, Cu-MEK activation, oxaliplatin, tetrathiomolybdate, disulfiram, ALDH1-positive tumor cells.
Abstract:
Background: Copper (Cu) is a transition metal active in Fenton redox cycling from reduced Cu+ and
H2O2, to oxidized Cu2+ and the hydroxyl radical (·OH) highly reactive oxygen species (ROS). At homeostatic Cu
levels, ROS promote cell proliferation, migration, angiogenesis, and wound repair. To limit ROS toxicity, cells
use Cu-dependent chaperone proteins, Cu-binding ceruloplasmin, and Cu-modulated enzymes like superoxide
dismutases (SOD) like SOD1 and SOD3 to scavenge excess superoxide anions which favour Cu+ reduction, and
mitochondrial cytochrome c oxidase, important in aerobic energy production. Because Cu helps drive tumor cell
proliferation by promoting growth factor-independent receptor tyrosine kinase signaling, and Cu-dependent
MEK1 involved in oncogenic BRAF-V600E signaling, further augmenting bioavailable Cu may promote ROS overproduction,
cancer progression and eventually tumor cell death. For these reasons, the following clinically approved
copper chelators are being repurposed as anti-cancer agents: a) ammonium tetrathiomolybdate (TTM)
used to treat Wilson’s disease (copper overload) and Menkes disease (copper deficiency); b) Disulfiram (DSF),
used against alcoholism, since it inhibits Aldehyde Dehydrogenase (ALDH1) enzyme, important in ethanol detoxification,
and a key target against cancer stem cells. Moreover, TTM and DSF are also relevant in cancer clinical
trials, because they increase the uptake of both Cu and Platinum (Pt)-containing anti-cancer drugs, since Pt
and Cu share the same CTR1 copper transporter.
Purpose: The majority of reports on Cu chelators dealt separately with either TTM, DSF or others. Here, we
compare in parallel, the anti-cancer efficacy of low doses of TTM and DSF, asking whether they can be synergistic
or antagonistic. The relevance of their unequal ROS inducing abilities and their different behavior as ionophores
is also addressed.
Significance: The potential of Cu chelators as repurposed anti-cancer drugs, should be greater in patients with
higher endogenous Cu levels. Since platinum and Cu share uptake receptors, the synergism by drugs containing
these metals should not be under-estimated. The potential of disulfiram or its metabolically active Cu-containing
form, to inhibit ALDH1-positive tumor cells is therapeutically very important.
