Contents

📒 Zhu 2016

Doxorubicin redox biology: redox cycling, topoisomerase inhibition, and oxidative stress1

Sciwheel

OVERVIEW

  • DOX’s mechanisms of action underlying cancer cell killing and induction of cardiotoxicity and heart failure, a major limiting factor of the drug’s clinical use, remain to be further elucidated
  • redox cycling in mitochondria, topoisomerase inhibition, and oxidative stress

OXIDATIVE STRESS

  • tightly regulated production of reactive oxygen species (ROS) is a fundamental mechanism of innate immunity and physiological homeostasis

Doxorubicin-Mediated Oxidative Stress

  • decreased expression of cellular antioxidant defenses
  • activation of ROS-generating enzymes/proteins, including NOX2 and Rac1
  • disruption of the mitochondrial electron transport chain (ETC) by doxorubicin either directly (cardiolipin insertion) or indirectly (mtDNA damage)

Nrf2 Signaling

  • Short term exposure to doxorubicin may cause activation of Nrf2 (nuclear factor E2-related factor 2), leading to transient increases in antioxidant gene expression

REDOX CYCLING

https://user-images.githubusercontent.com/40054455/96907373-bc9a1d80-14cd-11eb-9354-69b98f2e8463.png https://user-images.githubusercontent.com/40054455/96907388-c02da480-14cd-11eb-8cbb-3558dd380921.png

  • there is no direct evidence for doxorubicin to undergo redox cycling to generate ROS at pharmacologically relevant concentrations (0.1-1.0 μM) in target cells and tissues

TOPOISOMERASE INHIBITION

https://user-images.githubusercontent.com/40054455/86727443-07e30a00-c05e-11ea-82cb-07a45603ca06.png

  • Doxorubicin-induced anticancer activity from inhibition of TOP => dsDNA breaks
  • topoisomerase IIβ (TOP2B) in haert mitochondria are also affected. topoisomerase IIb serves as a mediator, rather than an ultimate target, of doxorubicin-induced cardiotoxicity https://user-images.githubusercontent.com/40054455/96907429-c9b70c80-14cd-11eb-8b5c-8db641bfa69d.png https://user-images.githubusercontent.com/40054455/96907422-c754b280-14cd-11eb-8f4e-4e8a344f4530.png
  • inhibit doxorubicin’s binding to topoisomerase IIb would be effective (e.g. dexrazoxane)

MOLECULAR TARGET-DRIVEN STRATEGIES FOR IMPROVING DOXORUBICIN’S THERAPEUTIC INDEX

  • so far no antioxidants have been shown to protect against doxorubicin’s cardiotoxicity or augment its anticancer activity in human cancer patients. (Not mito-targeted?)
  • dexrazoxane: iron chelator, inhibits DOX binding to topIIβ
  • novel agents that enhance doxorubicin-induced tumoricidal activity?

Reference


  1. Zhu H, Sarkar S, Scott L, et al. Doxorubicin redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React Oxyg Species (Apex) 2016;1(3):189-198. PMC5921833 ↩︎