ANTI-TUMOUR TREATMENTElevated copper and oxidative stress in cancer cells as a target for cancer treatment
Section snippets
Copper and cancer
Copper (Cu) is an essential trace element that plays a central role in the biochemistry of every living organism.1 In the body copper exists in both oxidation states, oxidized Cu (II) and reduced Cu (I).1 The unique electronic structure of copper allows it to serve as a co-factor in redox reactions of enzymes that carry out fundamental biological functions required for normal growth and development such as cytochrome c oxidase (involved in the mitochondrial electron transport chain), lysyl
Copper levels in the serum and tumor tissue of cancer patients
Several reports in the literature have shown that both serum and tumor copper levels in cancer patients are significantly elevated. A comprehensive literature review of copper levels reported in serum and tumor tissue of cancer patients compared to that in the healthy subjects is documented in Table 1, Table 2, respectively. A major percentage of these studies have focused on determining the concentrations of four important elements; copper, zinc, iron and selenium. The studies showed that
Copper and angiogenesis
‘Angiogenesis’ is defined as the process of development of new blood vessels. The concept that ‘tumor growth is dependent on angiogenesis’ was pioneered by Judah Folkman in the 1970–1980s. Tumor cells cannot grow more than 1–2 mm in diameter without angiogenesis, which supplies the tumor with oxygen and nutrients.28 Angiogenesis in a normal cell involves a complex interaction and balance between endogenous stimulators and inhibitors.28 Cancer cells have developed ways to either synthesize their
Copper chelators as anti-angiogenic agents
Copper reduction as an anti-cancer strategy is currently under intense investigation.40 Copper chelators such as d-pen,37 tetrathiomolybdate,41 clioquinol,42 and trientine43 have been shown to inhibit angiogenesis both in vitro and in vivo. Several animal studies have supported the hypothesis of employing copper chelators as anti-angiogenic agent. Pan et al.44 reported a synergistic effect on tumor growth of tetrathiomolybdate plus doxorubicin in a SUM149 murine xenograft. Khan et al.45
Oxidative stress and cancer
Each cell in the human body maintains a condition of homeostasis between the oxidant and antioxidant species. Both of these species types are very important for the normal metabolism, signal transduction and regulation of cellular functions.53 Oxidative stress could be simply defined as the disturbance in the oxidant-antioxidant balance, favoring the oxidant environment.54 Oxidative stress associated cellular damage has been indicated in a range of disorders such as cancer,55 diabetes mellitus,
Reactive oxygen species (ROS)
ROS can be simply defined as oxygen containing oxidizing agents. It has been reported that up to 1–3% of the pulmonary intake of oxygen by humans is converted into ROS.71 ROS are generally divided into two subgroups; free radicals such as superoxide radicals () and non-radical such as hydrogen peroxide (H2O2). Both radicals and non-radical ROS share the presence of an oxygen atom, which differentiates them from the reactive nitrogen species (RNS). Free radicals contain one or more unpaired
Hydrogen peroxide (H2O2)
H2O2 is freely miscible with water and most importantly it is known to freely diffuse through cell membranes.84 H2O2 is less reactive than its radical counterpart such as the superoxide and the hydroxyl radical, but due to the above mentioned ability to diffuse through membranes, H2O2 is a potent cellular oxidant species. The toxicity of H2O2 is largely based on its conversion to hydroxyl radical () either through ionizing radiation (as shown in reaction (a) below), by interaction with
ROS and cancer
In a normal cell, there exists a balance between the free radical generation and the antioxidant defense.94 It has long been documented that cancer cells are under increased and persistent oxidative stress due to elevated levels of intracellular ROS generation. The direct proof of oxidative stress in the cancer cells is shown through the analysis of significantly elevated levels of ROS such as H2O2, superoxide radical, while the indirect proof is shown through the existence of increased levels
Leukemia and oxidative stress
All forms of leukemia including Acute Lymphocytic Leukemia (ALL), Acute Nonlymphocytic Leukemia (ANLL), Chronic Myeloid Leukemia (CML) have been reported to have significantly increased levels of various ROS such as superoxide radical, H2O2, and alteration in the levels of enzymes such as SOD, glutathione peroxidase, glutathione reductase, and catalase compared to healthy subjects.19, 94 Additionally there have been studies showing that trace metals such as copper levels are significantly
Breast cancer and oxidative stress
Analogous to leukemia, there has been accumulating evidence in support of significantly higher oxidative stress in breast cancer patients.106 The excessive oxidative stress in breast cancer has been correlated to the severity of the disease e.g. Stage IV patients have been shown to have higher levels of oxidative stress compared to III, who have been shown to have higher levels of ROS stress compared to Stage II patients and so on for Stage I and control subjects.106
Khanzode et al. investigated
ROS in cancer treatment
In the last two decades ROS has been shown to be involved in each step of cancer development namely, initiation, promotion and progression.77, 112 Additionally, the levels of antioxidant enzyme such as catalase and SOD have been shown to be altered in tumor cells.113 It has been clearly documented that tumor cells are under persistent oxidative stress and the antioxidant system in the cancer cells are under constant attack, as they have to cope up with this excessive ROS being produced. Thus,
d-penicillamine and cancer treatment
d-penicillamine (d-pen) is an aminothiol, which was first identified as a product of penicillin hydrolysis in 1943 by Abraham. d-pen was introduced in the clinic as a copper chelating agent for the treatment of Wilson’s disease by Walshe in 1956.137 After more than 50 years of clinical use in the treatment of Wilson’s disease, d-pen is currently also used in the treatment of cystinuria, rheumatoid arthritis and heavy metal intoxication. d-pen is registered with the Food and Drug Administration
Conclusions
The presence of elevated levels of copper and oxidative stress in cancer patients compared to normal subjects has been well documented. The elevated copper and oxidative stress levels are hallmarks of range of malignancies, thus it provides for treatment approaches applicable to variety of malignant conditions. Therefore, there exist an opportunity to exploit these differences for the development of potential cancer treatment strategies. We have discussed the application of an established
Conflicts of interest statement
The authors declare there are no conflicts of interest.
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