Carcinoma and Oxidative Stress

Carcinoma and Oxidative Stress

The term anti-oxidant is commonly used and recommended as good for health. Lots of things inside the body and outside the body can cause damage via what is called oxidation. There is normally a balance maintained between free radical or reactive oxygen species (ROS) formation (which cause damage by oxidation) and endogenous antioxidant defense mechanisms in normal cells. Overproduction of ROS disrupts the balance leading to a condition called oxidative stress in the cells. Oxidative stress due to ROS-antioxidants imbalance causes injury to cells by oxidizing proteins, DNA and membrane lipids which can cause cell death.

ROS (or oxidation) is beneficial for cancer cells

Research in recent years has provided compelling evidences for the involvement of oxidative stress in large number of pathological states including carcinogenesis. In fact, oncogenic transformation, alterations in metabolic activity, and increased generation of ROS leads to increased oxidative stress in cancer cells compared to normal cells. Overproduction of ROS in cancer cells may cause the following:

1) Stimulate cellular proliferation,

2) Promote mutations and genetic instability and

3) Alter cellular sensitivity to anticancer agents.

These changes caused by ROS may contribute to the development of a heterogeneous cancer cell population and the emergence of drug-resistant cells during disease progression (by increasing DNA damage and mutations). Thus, ROS proves to be beneficial for the growth of cancer cells.

Possible mechanisms of ROS generation in cancer cells

There can be several mechanisms for increased generation of ROS in cancer cells. These can be summarized under the following broad categories:

1) Oncogenic signals: Recent studies have shown that oncogenic signals can be responsible for increased ROS generation in cancer cells. Oncogenes are genes that can be responsible for cells becoming cancerous.

2) Malfunction of the mitochondrial respiratory chain: Mutations in mitochondrial DNA (the mitochondria are the powerhouses of cells) are often detected in cancer cells. This can be a cause of increased ROS generation in cancer cells. ROS generation is much higher in cancer calls than normal cells.

3) Chronic inflammation and extracellular ROS: Chronic inflammation due to certain infections (chronic hepatitis and H. pylori infections in stomach) leads to infiltration of certain kinds of white blood cells at the site of inflammation. These immune calls generate ROS as a part of their mechanism of killing pathogens. Therefore, chronic inflammation can lead to sustained ROS generation resulting in protein, lipid and DNA damage to a great extent.

Therapeutic implications of oxidative stress START HERE

ROS generation is enhanced in cancer cells due to the above reasons, which is why they help in development of cancer progression and metastasis. However, we know that ROS can also cause severe cellular damage. The cancer cells maintain a fine balance between ROS generation and production of endogenous antioxidants, which can neutralize these ROS. This gives an opportunity to kill cancer cells by disrupting this balance.

Recently, new therapeutic strategies that take advantage of increased reactive oxygen species or inhibition of endogenous antioxidant defense, hence producing a state of oxidative stress selectively in cancer cells, have gained importance. Oxidative stress is not always detrimental. Selective oxidative stress sometimes is desirable and can be utilized therapeutically. There are numerous drugs which are known to act by the mechanism of oxidative stress and can be utilized therapeutically.

Strategies to cause further ROS stress in cancer cells to inflict lethal damage or trigger cell death include:

(1) Direct exposure of cancer cells to ROS-generating agents,

(2) Inhibition of antioxidant enzymes,

(3) Reduction of cellular oxidant-buffering capacity, and

(4) Appropriate combinations of the above.

Because normal cells appear to have low levels of ROS stress and reserve a higher capacity to cope with further oxidative insults than cancer cells, it is possible to use agents that directly or indirectly cause ROS accumulation to preferentially kill cancer cells and improve therapeutic selectivity.

Potential Drugs for cancer based on increasing oxidative stress

Direct ROS generating agents: Examples of therapeutic agents with this strategy are cisplatin, bleomycin, natural anthraquinones (Emodin), anthracyclines (Daunorubicin, Doxorubicin) and irradiation.

Inhibitor of antioxidant enzymes: Arsenic trioxide and 2-ME can lead to increased production of ROS and subsequent killing of cancer cells indirectly.

Impairment of redox buffering: GSH is an endogenous buffer in cancer cells which can protect them from several chemotherapeutic agents. GSH can be lowered in these cells by Buthionine sulfoximime (BSO). Lowering the GSH content in cells leads to an increase in the reactive oxygen species (ROS) production. This potentiates the ability to kill cancer cells by a number of chemotherapeutic agents, including cisplatin, for example. Studies support the strategy of combining a GSH-depleting agent with chemotherapy to improve responses.

Future perspectives

Exploitation of the inherent oxidative stress in cancers can be a novel therapeutic approach to treat cancer. The therapeutic manipulation of the ROS levels could involve using agents that directly increase ROS production, or ones that inhibit antioxidant defenses, or their combinations. Characterization of the redox status of cancer cells is required to select cancers that can be treated with these pharmacological agents. Cancers that exhibit high oxidative stress through generation of high levels of ROS and reduction of endogenous antioxidant levels can be potentially treated with these ROS-generating agents.

Selective production of oxidative stress in cancer cells is a major concern. Further studies are required in this field and more clinical trials should be conducted to prove therapeutic efficacy and selectivity of these potential anticancer agents.

References

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  9. This article was originally published on September 3, 2012 and last revision and update was 9/4/2015.