Elevated copper and oxidative stress in cancer cells as a target for cancer treatment

doi:10.1016/j.ctrv.2008.07.004

Cancer Treatment Reviews

Volume 35, Issue 1, February 2009, Pages 32-46

https://doi.org/10.1016/j.ctrv.2008.07.004 Get rights and content

Summary

As we gain a better understanding of the factors affecting cancer etiology, we can design improved treatment strategies. Over the past three to four decades, there have been numerous successful efforts in recognizing important cellular proteins essential in cancer growth and therefore these proteins have been targeted for cancer treatment. However, studies have shown that targeting one or two proteins in the complex cancer cascade may not be sufficient in controlling and/or inhibiting cancer growth. Therefore, there is a need to examine features which are potentially involved in multiple facets of cancer development. In this review we discuss the targeting of the elevated copper (both in serum and tumor) and oxidative stress levels in cancer with the aid of a copper chelator d-penicillamine (d-pen) for potential cancer treatment. Numerous studies in the literature have reported that both the serum and tumor copper levels are elevated in a variety of malignancies, including both solid tumor and blood cancer. Further, the elevated copper levels have been shown to be directly correlated to cancer progression. Enhanced levels of intrinsic oxidative stress has been shown in variety of tumors, possibly due to the combination of factors such as elevated active metabolism, mitochondrial mutation, cytokines, and inflammation. The cancer cells under sustained ROS stress tend to heavily utilize adaptation mechanisms and may exhaust cellular ROS-buffering capacity. Therefore, the elevated copper levels and increased oxidative stress in cancer cells provide for a prospect of selective 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 ( $O_{2}^{-}$ ) 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 ( $^{} OH$ ) 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.

References (156)

Z.H. Harris et al.
Genetic and molecular basis of copper toxicity
Am J Clin Nutr
(1996)
H. Tapiero et al.
Trace elements in human physiology and pathology
Copper Biomed Pharmcother
(2003)
L.M. Gaetke et al.
Copper toxicity, oxidative stress, and antioxidant nutrients
Toxicology
(2003)
B. Lonnerdal
Bioavailability of copper
Am J Clin Nutr
(1996)
J.R. Turnlund
Human whole body copper metabolism
Am J Clin Nutr
(1998)
M.C. Linder et al.
Copper transport
Am J Clin Nutr
(1998)
G. Brewer
Anticopper therapy against cancer and diseases of inflammation and fibrosis
Drug Dis Today
(2005)
F.K. Habib et al.
The zinc and copper content of blood leukocytes and plasma from patients with benign and malignant prostates
Clin Chim Acta
(1980)
K. Camphausen et al.
Evaluation of chelating agents as anti-angiogenic therapy through copper chelation
Bioorg Med Chem
(2004)
M.K. Khan et al.
Radiotherapy and antiangiogenic TM in lung cancer
Neoplasia (New York, NY)
(2002)

J. Chandra et al.

Triggering and modulation of apoptosis by oxidative stress

Free Rad Med Biol

(2000)

P. Dandona et al.

Oxidative damage to DNA in diabeted mellitus

Lancet

(1996)

M. Valko et al.

Free radicals and antioxidants in normal physiological functions and human disease

Int J Biochem Cell Biol

(2007)

P. Jenner

Oxidative damage in neurodegenerative diseases

Lancet

(1994)

U. Nair et al.

Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans

Free Rad Biol Med

(2007)

L. Gate et al.

Oxidative stress induced in pathologies: the role of antioxidants

Biomed Pharmcother

(1999)

H.P. Monteiro et al.

Redox modulation of tyrosine phosphorylation-dependent signal transduction pathways

Free Rad Biol Med

(1996)

T.D. Oberley

Oxidative damage and cancer

Am J Path

(2002)

A.C. Nulton-Persson

Modulation of mitochondrial function by hydrogen peroxide

J Biol Chem

(2001)

L. Castro

Reactive oxygen species in human health and disease

Nutrition

(2001)

M. Valko et al.

Free radicals, metals and antioxidants in oxidative stress-induced cancer

Chemico-Biol Interact

(2006)

B. Halliwell et al.

Hydrogen peroxide in the human body

FEBS Lett

(2000)

S.A. Aust et al.

Role of metals in oxygen radical reactions

J Free Rad Biol Med

(1985)

G.R. Buettner

The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate

Arch Biochem Biophys

(1993)

K. Sasaki et al.

Kinetics of hydrogen peroxide elimination by human umbilical vein endothelial cells in culture

Biochem Biophys Acta

(1998)

F. Antunes et al.

Estimation of H₂O₂ gradient across biomembranes

FEBS Lett

(2000)

R.H. Burdon

Superoxide and hydrogen peroxide in relation to mammalian cell proliferation

Free Rad Med Biol

(1995)

A. Gupte et al.

Copper chelation by d-penicillamine generates reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells

Free Rad Biol Med

(2007)

G.S. Devi et al.

Free radicals antioxidant enzymes and lipid peroxidation in different types of leukemia

Clin Chim Acta

(2000)

H. Pelicano et al.

ROS stress in cancer cells and therapeutic implications

Drug Resist Updates

(2004)

L. Chaiswing et al.

Characterization of redox state of two human prostate carcinoma cell lines with different degrees of aggressiveness

Free Rad Biol Med

(2007)

S. Kondo et al.

Persistent oxidative stress in human colorectal carcinoma, but not adenoma

Free Rad Biol Med

(1999)

K. Senthil et al.

Evidence of oxidative stress in the circulation of ovarian cancer patients

Clin Chim Acta

(2004)

A. Aydin et al.

Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostatic hyperplasia

Clin Biochem

(2006)

M. Valko et al.

Metals, toxicity and oxidative stress

Curr Med Chem

(2005)

T. Wang et al.

Copper in medicine: homeostasis, chelation therapy and anti-tumor drug design

Curr Med Chem

(2006)

N.E. Hellman et al.

Ceruloplasmin metabolism and function

Ann Rev Nutr

(2002)

V.L. Goodman et al.

Copper deficiency as an anti-cancer strategy

Endocr Relat Cancer

(2004)

S. Apelgot et al.

Altered distribution of copper (⁶⁴Cu) in tumor-bearing mice and rats

Anticancer Res

(1986)

B. Semczuk et al.

Serum copper level in patients with laryngeal carcinoma

Otolaryngial Pol

(1973)

P. Tani et al.

Serum iron, copper and iron binding capacity in bronchogenic pulmonary carcinoma

Scand J Res Dis

(1972)

K.W. Kuo et al.

Serum and tissue trace elements in patients with breast cancer in Taiwan

Biol Trace Elem Res

(2002)

M. Hrgovic et al.

Cancer

(1973)

M.C. Linder et al.

Tumori

(1981)

A. Scanni et al.

Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung

Tumori

(1977)

X.L. Zuo et al.

Levels of selenium, zinc, copper and antioxidant enzyme activity in patients with leukemia

Biol Trace Elem Res

(2006)

A. Chan et al.

Serum ultrafiltrable copper, total copper and ceruloplasmin concentrations in gynecological carcinoma

Ann Clin Biochem

(1993)

M. Diez et al.

Serum and tissue trace metal levels in lung cancer

Oncology

(1989)

E.J. Margalioth et al.

Copper and zinc levels in normal and malignant tissues

Cancer

(1983)

V.S. Rajput et al.

An evaluation of serum copper levels in diagnosis of various malignancies

Indian J Surg

(1979)

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ANTI-TUMOUR TREATMENTElevated copper and oxidative stress in cancer cells as a target for cancer treatment

Summary

Section snippets

Copper and cancer

Copper levels in the serum and tumor tissue of cancer patients

Copper and angiogenesis

Copper chelators as anti-angiogenic agents

Oxidative stress and cancer

Reactive oxygen species (ROS)

Hydrogen peroxide (H2O2)

ROS and cancer

Leukemia and oxidative stress

Breast cancer and oxidative stress

ROS in cancer treatment

d-penicillamine and cancer treatment

Conclusions

Conflicts of interest statement

Am J Clin Nutr

Copper Biomed Pharmcother

Toxicology

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Drug Dis Today

Clin Chim Acta

Bioorg Med Chem

Neoplasia (New York, NY)

Free Rad Med Biol

Lancet

Int J Biochem Cell Biol

Lancet

Free Rad Biol Med

Biomed Pharmcother

Free Rad Biol Med

Am J Path

J Biol Chem

Nutrition

Chemico-Biol Interact

FEBS Lett

J Free Rad Biol Med

Arch Biochem Biophys

Biochem Biophys Acta

FEBS Lett

Free Rad Med Biol

Free Rad Biol Med

Clin Chim Acta

Drug Resist Updates

Free Rad Biol Med

Free Rad Biol Med

Clin Chim Acta

Clin Biochem

Metals, toxicity and oxidative stress

Curr Med Chem

Copper in medicine: homeostasis, chelation therapy and anti-tumor drug design

Curr Med Chem

Ceruloplasmin metabolism and function

Ann Rev Nutr

Copper deficiency as an anti-cancer strategy

Endocr Relat Cancer

Altered distribution of copper (64Cu) in tumor-bearing mice and rats

Anticancer Res

Serum copper level in patients with laryngeal carcinoma

Otolaryngial Pol

Serum iron, copper and iron binding capacity in bronchogenic pulmonary carcinoma

Scand J Res Dis

Serum and tissue trace elements in patients with breast cancer in Taiwan

Biol Trace Elem Res

Cancer

Tumori

Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung

Tumori

Levels of selenium, zinc, copper and antioxidant enzyme activity in patients with leukemia

Biol Trace Elem Res

Serum ultrafiltrable copper, total copper and ceruloplasmin concentrations in gynecological carcinoma

Ann Clin Biochem

Serum and tissue trace metal levels in lung cancer

Oncology

Copper and zinc levels in normal and malignant tissues

Cancer

An evaluation of serum copper levels in diagnosis of various malignancies

ANTI-TUMOUR TREATMENT
Elevated copper and oxidative stress in cancer cells as a target for cancer treatment

Hydrogen peroxide (H₂O₂)

Altered distribution of copper (⁶⁴Cu) in tumor-bearing mice and rats