Human Protein May Prevent Castration-Resistant Prostate Cancer

The natural protein endostatin was observed to reduce the proliferation of castration-resistant prostate cancer cells, according to a study published by The FASEB Journal. The authors also discovered the pathways and signaling caused by endostatin treatment, and are now testing it in a preclinical trial to further determine its actions.

"We hope we can delay the onset of castration-resistant disease," said Selvarangan Ponnazhagen, PhD.

Androgen deprivation therapy is typically used to treat prostate cancer. This treatment depletes prostate cancer cells of androgens and creates oxidative stress in the cells. The oxidative stress is linked to reactivated signaling in the androgen receptors, and can cause castration-resistant disease. Patients who develop castration-resistant prostate cancer typically have poor health outcomes and few treatment options.

The authors speculated that oxidative stress can be activated upstream of the androgen receptor, with the glucorticoid receptor as the stress-inducer, according to the study. If this is observed to be true, the researchers believe that endostatin may remove oxidative stress by interacting with the glucorticoid receptor. This could reduce pro-tumorigenic function in the cells, and prevent the onset of resistant disease.

The investigators found that endostatin targeted the androgen and glucorticoid receptors, as they had hypothesized. Endostatin was observed to target the receptors through reciprocal regulation that affected downstream pro-oxidant signaling, according to the study.

Treatment with endostatin was discovered to reduce the steroid hormone receptor levels possibly through interaction with the androgen and glucorticoid receptors. These changes were observed to lead to psychological changes that removed oxidative stress.

The authors found that endostatin treatment upregulated the major cellular machinery to scavenge destructive reactive-oxygen-species, such as manganese superoxide dismutase, the gluthathione system and the biliverdin/bilirubin redox cycle, according to the study.

The increased levels of reduced glutathione, an antioxidant, also increased glucose intake as the cancer cells moved to the pentose phosphate pathway, which uses glucose to maintain the antioxidant system, including NAD/NADP production and gluthaione, according to the study.

These findings suggest that endostatin treatment may be an effective way to prevent or slow castration-resistant prostate cancer, which can be a lethal and has few treatment options. This treatment option may also come up fewer side effects than chemotherapy or radiation due to the protein naturally occurring in humans.

"Our study suggests that the potential therapeutic application of endostatin may include combination with the frontline androgen-deprivation therapy that targets prostate cancer at early stages," the authors wrote. "Based on the known anti-angiogenic properties of endostatin and on more interesting evidence that human prostate endothelial cells also express androgen receptor, the application of endostatin in combination therapies could synergize tumoristatic and tumoricidal effects with minimal resistance."