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Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

Key Points

  • The effectiveness of current gene-targeting therapeutic strategies is limited by the drug resistance and the genomic instability that cancer cells acquire.

  • Most cancer cells exhibit increased aerobic glycolysis and oxidative stress — features that could be important in the development new anticancer strategies.

  • An increase in reactive oxygen species (ROS) is associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis, due either to an elevation of ROS production or to a decline of ROS-scavenging capacity.

  • If the increase of ROS reaches a certain threshold level that is incompatible with cellular survival, ROS may exert a cytotoxic effect, leading to the death of malignant cells and thus limiting cancer progression. However, under persistent intrinsic oxidative stress, many cancer cells become well-adapted to such stress and develop an enhanced, endogenous antioxidant capacity.

  • Abrogation of this adaptation mechanism with 'pro-oxidant' agents could be an attractive strategy to preferentially affect cancer cells and could have significant therapeutic implications.

  • Because radiation and many conventional cytotoxic anticancer drugs can also directly or indirectly increase ROS levels in cancer cells, combination of radiotherapy or standard chemotherapy with agents that abrogate antioxidant systems in cancer cells should also be explored.

  • Finally, the undefined, possibly unique, redox biology of cancer stem cells suggests that redox-modulating strategies could represent an effective strategy to combat this highly drug-resistant population of cells.

Abstract

Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

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Figure 1: Schematic illustration of cellular redox homeostasis.
Figure 2: Regulation of protein functions through redox-mediated mechanisms.
Figure 3: The vicious cycle of ROS stress in cancer.
Figure 4: Redox adaptation in cancer development and drug resistance.
Figure 5: Targeting cancer cells through ROS-mediated mechanisms.
Figure 6: Redox-modulating strategies to selectively kill cancer cells and overcome drug resistance.

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Acknowledgements

Contributions to the scientific reports cited in this work were supported in part by grants CA085563, CA100428 and CA109041 to P.H. from the National Institutes of Health and a research grant from the CLL global research foundation. D.T. is a recipient of a scholarship from the Anandamahidol Foundation under the royal patronage of His Majesty the King of Thailand, and a recipient of the Lummis Family Fellowship in Biomedical Sciences.

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Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?. Nat Rev Drug Discov 8, 579–591 (2009). https://doi.org/10.1038/nrd2803

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