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Published on: February 7, 2018
Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity
Elizabeth Oldham Hileman1, Jinsong Liu, Maher Albitar
1Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Purpose:
Therapeutic selectivity is one of the most important considerations in cancer chemotherapy. The design of therapeutic strategies to preferentially kill malignant cells while minimizing harmful effects to normal cells depends on our understanding of the biological differences between cancer and normal cells. We have previously demonstrated that certain agents generating reactive oxygen species (ROS) such as 2-methoxyestradiol (2-ME) preferentially kill human leukemia cells without exhibiting significant cytotoxicity in normal lymphocytes. The purpose of the current study was to investigate the biochemical basis for such selective anticancer activity.
Methods:
Flow cytometric analyses were utilized to measure intracellular O(2)(-) levels and apoptosis. MTT assays were used as indicators of cellular viability. Western blot analysis was used to measure the expression of antioxidant enzymes in cancer and normal cells.
Results:
Malignant cells in general are more active than normal cells in the production of O(2)(-), are under intrinsic oxidative stress, and thus are more vulnerable to damage by ROS-generating agents. The intrinsic oxidative stress in cancer cells was associated with the upregulation of SOD and catalase protein expression, likely as a mechanism to tolerate increased ROS stress. The increase in SOD and catalase expression was observed both in primary human leukemia cells and in primary ovarian cancer cells. Both malignant cell types were more sensitive to 2-ME than their normal counterparts, as demonstrated by the significant accumulation of O(2)(-) and subsequent apoptosis. The administration of ROS scavengers in combination with 2-ME prevented the accumulation of O(2)(-) and abrogated apoptosis induction.
Conclusions:
O(2)(-) is an important mediator of 2-ME-induced apoptosis. The increased oxidative stress in cancer cells forces these cells to rely more on antioxidant enzymes such as SOD for O(2)(-) elimination, thus making the malignant cells more vulnerable to SOD inhibition than normal cells.
Insights
Reactive oxygen species (ROS) selectively kill cancer cells by exploiting their increased oxidative stress. Cancer cells
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Therapeutic selectivity is crucial in cancer chemotherapy, aiming to eliminate malignant cells while sparing normal tissues.
- Previous studies indicated that reactive oxygen species (ROS)-generating agents, like 2-methoxyestradiol (2-ME), selectively kill human leukemia cells.
- Understanding the biochemical underpinnings of this selective anticancer activity is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the biochemical mechanisms responsible for the selective killing of cancer cells by ROS-generating agents.
- To elucidate the role of oxidative stress and antioxidant enzymes in the differential sensitivity of cancer versus normal cells to 2-ME.
Main Methods:
- Flow cytometry was used to quantify intracellular superoxide anion (O2(-)) levels and assess apoptosis.
- Cellular viability was determined using MTT assays.
- Western blot analysis measured the expression levels of key antioxidant enzymes, such as superoxide dismutase (SOD) and catalase.
Main Results:
- Malignant cells exhibit higher basal O2(-) production and intrinsic oxidative stress compared to normal cells.
- Cancer cells, including leukemia and ovarian cancer cells, upregulate SOD and catalase expression to cope with increased ROS.
- 2-ME treatment led to significant O2(-) accumulation and apoptosis in malignant cells, with less effect on normal cells; ROS scavengers mitigated these effects.
Conclusions:
- Superoxide anion (O2(-)) is a key mediator of 2-ME-induced apoptosis in cancer cells.
- Elevated oxidative stress in cancer cells increases their dependence on antioxidant enzymes like SOD, making them more susceptible to agents that target these pathways.
- This differential vulnerability presents a promising strategy for selective cancer chemotherapy.
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