Oxidative Stress in Prostate Cancer

Changing Research Concepts Towards a Novel Paradigm for Prevention and Therapeutics

A Paschos; R Pandya; W C M Duivenvoorden; J H Pinthus

Disclosures

Prostate Cancer Prostatic Dis. 2013;16(3):217-225. 

In This Article

Potentiating Radiation and Chemotherapy Using Antioxidants

Radiation and certain classes of chemotherapy drugs act to induce oxidative stress by the generation of free radicals to damage DNA and proteins, and eventually cell death. Chronic oxidative stress as seen in PC cells may lead to adaptation to oxidative stress-based therapeutics.[32,72] This adaptation mechanism is based on the increased expression and activation of stress molecules and antioxidative machinery to negotiate the elevated levels of ROS. However, these cells also become less sensitive to ROS generated by oxidative stress-based therapies, such as radiation or photodynamic therapy. Activation of phospho-p38 and pAKT, and increased expression of clusterin, catalase and manganese superoxide dismutase occurs in PC cells in response to androgen-induced oxidative stress, and becomes reversible through androgen deprivation or through incubation with a reducing agent, which also restores the sensitivity of the cells to radiation.[32] Thus, reducing basal levels of ROS in PC cells may facilitate the therapeutic effects of oxidative stress-based therapies and in particular radiation. Although the advantage of androgen deprivation in this respect is well established,[73] clinical studies with respect to the application of antioxidants as radiation sensitizers are lacking. Antioxidants may also protect healthy tissues and lower the incidence of treatment-related side effects. A systematic review by Tabassum et al.[74] provides evidence that antioxidant supplementation during chemotherapy may potentially reduce dose-limiting toxicity.

The development of resistance is a major obstacle for effective treatment in PC, as in other cancers. Recently, clusterin has appeared as a major contributor to the development of resistance against numerous apoptosis-inducing agents by acting as a cytoprotective survival protein. Intracellular clusterin expression increases with Gleason score,[75] is even higher in castration-resistant tumors and is upregulated after hormonal therapy.[76] Oxidative stress causes a positive adaptive response on clusterin expression.[77] In vitro using different ROS-related treatment modalities, overexpression of clusterin in LNCaP cells leads to less sensitivity to radiation[78] and to decreased H2O2-induced apoptosis and concomitant increased DNA damage.[79] Interestingly, only cytoplasmic bu not nuclear clusterin exerts these effects. In LNCaP and PC-3 cells, resistance to paclitaxel is mediated by the paclitaxel-induced transactivation of clusterin expression through an increase in YB-1.[80]

processing....