56 - Short and Long-term Tempol Treatments in TRAMP Model: Differential PCa Responses Related to Oxidative Stress, Angiogenesis and Glandular Stroma

Poster Board Number: 56
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Abstract Body : Introduction and Objective: Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second most common cause of death among men in the United States and Brazil. PCa is associated to different molecular mechanisms that involve chronic inflammation and a multitude of reactive nitrogen and oxygen species, leading to oxidative imbalance; uncontrolled cellular proliferation; stromal alterations; and proangiogenic process. Tempol is a redox-cycling nitroxide that participates in the metabolism of various reactive oxygen species (ROS) and is considered a potent antioxidant. However, few studies have reported the use of tempol in PCa. The present study investigated the effects of short and long-term tempol treatments in different stages of cancer progression using the TRAMP model. Materials and Methods: Molecules related to oxidative stress, stromal remodeling and angiogenic process were evaluated. To do so, the Tramp mice were distributed into 6 experimental groups: short-term tempol treatment groups at an early stage (Control (C)-8-12 and Tempol (T)-8-12 groups) and late stage (Control (C)-16-20 and Tempol (T)-16-20 groups) of PCa progression; and another 2 experimental groups: long-term tempol treatments (Control (C)-8-16 and Tempol (T)-8-16 groups) (. The tempol groups were treated with 50 mg/kg tempol doses for four weeks. All control groups received water as a vehicle and followed the Ethics Committee on Animal Use (CEUA-/UNICAMP/5115-1/2019 and 5115-1(A)-2020). The ventral and dorsolateral lobes of the prostate were collected and submitted to immunohistochemical and western blotting analyses. Results: The results showed that short-term tempol treatment increased SOD2 protein levels in the T8-12 and T16-20 groups. In contrast, tempol did not change Catalase and 4-HNE levels in the short-term treatment groups. The vimentin protein levels increased in the early stage groups after short-term treatments. In the late stage group, the short-term tempol treatment decreased vimentin, VE-caderin and HIF-1α. The pro-angiogenic factor, VEGF and growth factor, TGF-β1 increased after short-term treatment in the late stage of cancer progression. The long-term tempol treatment increased VEGFR2, VEGF, TGF-β1, vimentin and VE-caderin. Conclusion: To conclude, tempol plays a multifaceted role in the prostatic tissue environment, showing a beneficial therapy in the PCa treatment, delaying PCa, particularly, in the early and late stages of cancer progression submitted to short-term treatments. In contrast, tempol stimulated pro-angiogenic factors and glandular stromal imbalance in the long-term treatment, pointing out dependent-tissue response of the prostatic lesion stages and the length of the treatment period. Significance/Implication: The mechanisms related to PCa are complex and dependent on epithelium-stroma interactions. Thus, studying different drugs and showing the molecular responses according to cancer progression, as is the case of Tempol, could really help to improve PCa treatments and also further research will be useful to obtain more details about the tempol effects in PCa angiogenesis and oxidative stress.
Funding Sources: São Paulo Research Foundation, FAPESP (2021/02108-0 and 2018/21647-6)