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Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity

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Abstract

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 O2 − 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 O2 −, 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 O2 − and subsequent apoptosis. The administration of ROS scavengers in combination with 2-ME prevented the accumulation of O2 − and abrogated apoptosis induction.

Conclusions

O2 − 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 O2 − elimination, thus making the malignant cells more vulnerable to SOD inhibition than normal cells.

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Fig. 1A–G
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Abbreviations

CLL:

Chronic lymphocytic leukemia

2-ME:

2-Methoxyestradiol

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

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Author information

Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA

    Elizabeth Oldham Hileman & Peng Huang

  2. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Jinsong Liu

  3. Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Maher Albitar

  4. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Michael J. Keating

Authors
  1. Elizabeth Oldham Hileman
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  2. Jinsong Liu
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  3. Maher Albitar
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  4. Michael J. Keating
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  5. Peng Huang
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Corresponding author

Correspondence to Peng Huang.

Additional information

This study was supported in part by research grants CA77339 and CA85563 from the National Cancer Institute/National Institutes of Health, and a training Grant CA67759 from the National Cancer Institute.

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Hileman, E.O., Liu, J., Albitar, M. et al. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol 53, 209–219 (2004). https://doi.org/10.1007/s00280-003-0726-5

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  • DOI: https://doi.org/10.1007/s00280-003-0726-5

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