ReviewAnticopper therapy against cancer and diseases of inflammation and fibrosis
Section snippets
Anticopper action of tetrathiomolybdate
TM was developed to fill a therapeutic niche in Wilson's disease, that of initial treatment of those patients presenting with brain damage from copper toxicity [3]. Penicillamine and trientine have a high risk of causing further neurologic deterioration in this type of patient, and zinc is too slow acting. TM acts by forming a tripartite complex with copper and many types of proteins. Given with meals, it complexes copper with food proteins and thereby prevents the absorption of copper. Both
Antiangiogenesis and cancer
Folkman and his associates [7] are generally credited with the concept that tumor growth is dependent upon angiogenesis. Cancer cells can grow into a small mass 1-2 mm in diameter without a blood supply, but to grow further, the tumor must develop a blood supply to nourish cells not near the surface. Antiangiogenesis is attractive as an anticancer approach because there is little angiogenesis in normal tissue. In the past 15 years there has been a great deal of activity to develop
Tetrathiomolybdate therapy
Other diseases where excessive angiogenesis is believed to be part of the pathogenesis include retinopathy, such as diabetic retinopathy and retinopathy of prematurity, wet type macular degeneration, rheumatoid arthritis and psoriasis.
A ten-patient open study of TM in macular degeneration found no apparent efficacy [31]. However, TM has shown positive results in a mouse model of retinopathy of prematurity, inhibiting both neovascularization and VEGF expression [32].
Therapy with other anticopper drugs
None of the other anticopper
Preclinical studies
It has been hypothesized [33, 34] that the pathway of fibrosis (Figure 1) might be copper dependent, based first on the known copper dependence of secreted protein acidic and rich in cysteine (SPARC), and second, on the high cysteine content of connective tissue growth factor (CTGF), often a predictor of copper binding. To test this hypothesis, TM therapy was first tried in the bleomycin mouse model of pulmonary fibrosis. (In all of the animal studies described the dose of oral TM was such that
Conclusions and outlook
We have presented evidence that TM, through a copper-lowering effect, has efficacy in cancer, in diseases of fibrosis and in diseases of inflammation. The mechanism in cancer is through antiangiogenesis. Inhibition of tumour growth by TM is probably mediated by blocking angiogenesis. TM's mechanism of antiangiogenesis appears to involve NFκB inhibition, although in addition, certain angiogenic promoters appear to be directly copper dependent. TM's antiinflammatory mechanism may also involve
Conflict of interest acknowledgement
The University of Michigan has recently licensed the antiangiogenic uses of TM to Attenuon LLC, San Diego, CA. and Brewer has equity in and is a paid consultant to Attenuon LLC.
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2021, Journal of ProteomicsCitation Excerpt :Notably, serum CP is used as a marker of copper status to monitor copper levels [86]. Copper is an essential trace element and a key component of many enzymes that seems to play a crucial role in the development of inflammatory and fibrotic diseases [87] due to the fact that many cytokines are copper dependent, such as TGFβ, TNFα, IL1β and SPARC [88]. The copper chelator tetrathiomolybdate (TM) has shown promising results in reducing PF, partly by reducing protein levels of lysyl oxidase (LOX), a copper-dependent enzyme responsible for crosslinking the ECM [86,89].
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