Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

Abstract

combined androgen deprivation therapy (AdT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. A total of 64 participants with NMPc were enrolled. Fatigue was assessed using the Functional Assessment of cancer Therapy-Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMcs) extracted from participants' whole blood. An AdT/RT-induced fatigue mouse model was developed, with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the AdT/RT mouse brains using western blot analysis of glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). The results demonstrated that fatigue in the AdT group was exacerbated during RT compared with the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMcs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The AdT/RT mice demonstrated the synergistic effect of AdT and RT in decreasing VWRA. Brain tissues of AdT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. In conclusion, these findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (cNS). The synergistic effect of AdT/RT is behaviorally reproducible in a mouse model and its mechanism may be related to bioenergetics in the cNS.

Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression

“…Whole extracted brains were flash-frozen in liquid nitrogen. Lysates were made in the same manner as previously reported [23]. The samples were denatured at 100˚C for 5 minutes and loaded onto 4-20% Mini-PROTEAN 1 TGX™ Precast Gels (Bio-Rad, Hercules, CA, USA).…”

Steroid Hormone Biosynthesis Metabolism Is Associated With Fatigue Related to Androgen Deprivation Therapy for Prostate Cancer

“…In fact, mitochondrial dysfunction is often secondary to a disruption of carnitine homeostasis (Sharma and Black, 2009). ADTinduced changes in metabolites related to carnitine synthesis and mitochondrial fatty acid oxidation may help explain our previous observation of mitochondrial dysfunction in fatigued patients (Feng et al, 2020). Another pathway of interest that was associated with metabolites that significantly discriminated between the two groups was glutathione metabolism (Figure 1E), including cysteinylglycine and oxidized cys-gly (Figure 3B).…”

A Prospective Study of the Relationship Between Clinical Outcomes After Enzalutamide and Serum Androgen Levels Measured via Liquid Chromatography-tandem Mass Spectrometry in Patients with Castration-resistant Prostate Cancer

“…The underlying mechanism remains poorly understood. Feng et al [27] showed that combination ADT and radiation therapy worsened fatigue and was associated with anemia and mitochondrial dysfunction. By contrast, Bandara et al [28] used multivariate models with fatigue as the outcome and found that neither hemoglobin nor T levels had a significant within-patient effect on fatigue developing during ADT/radiation therapy.…”